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date: 18 August 2019

Pesticides and Human Health

Abstract and Keywords

The fight against agricultural and household pests accompanies the history of humanity, and a total ban on the use of pesticides seems unlikely to happen in the foreseeable future. Currently, about 100,000 different chemicals, inorganic and organic, are currently in the market, grouped according to their function as insecticides, herbicides, fungicides, fumigants, rodenticides, fertilizers, growth regulators, etc. against specific pests, such as snails or human parasites, or their chemical structure—organochlorines, organophosphates, pyrethroids, carbamates, dithiocarbamates, organotin compounds, phthalimides, phenoxy acids, heterocyclic azole compounds, coumarins, etc. Runoff from agricultural land and rain precipitation and dry deposition from the atmosphere can extend exposure to the general environment through the transport of pesticides to streams and ground-water. Also, the prolonged bio-persistence of organochlorines generates their accumulation in the food chain, and their atmospheric drift toward remote geographical areas is mentioned as the cause of elevated fat contents in Arctic mammals. Current regulation in the developed world and the phasing out of more toxic pesticides have greatly reduced the frequency of acute intoxications, although less stringent regulations in the developing world contribute to a complex pattern of exposure circumstances worldwide. Nonetheless, evidence is growing about long-term health effects following high-level, long-lasting exposure to specific pesticides, including asthma and other allergic diseases, immunotoxicity, endocrine disruption, cancer, and central and peripheral nervous system effects. Major reasons for uncertainty in interpreting epidemiological findings of pesticide effects include the complex pattern of overlapping exposure due to multiple treatments applied to different crops and their frequent changes over time to overcome pest resistance. Further research will have to address specific agrochemicals with well-characterized exposure patterns.

Keywords: pesticides, environmental health, occupational health, asthma, immunotoxicity, endocrine disruption, cancer, nervous system disorders

Introduction

. . . Old woman, bring some sulfur, and make a fire,

so I can purge the hall from this pollution . . .

My child, . . . let me bring you a tunic and cloak to wear.

It would be wrong to stand there in your hall

with your broad shoulders clothed in rags.

Homer, Odyssey, Book 22, 611–627

Brief Historical Notes

Methods to fight agricultural and household pests were known and applied as long ago as 4500 bc. The Ebers Papyrus, written by Egyptian alchemists in 1550 bc, lists over 800 recipes as pesticides. Homer cites the use of sulfur as a disinfesting agent and the need for protective clothing when using it, even before the Chinese were aware of the insecticidal properties of the arsenicals. Pliny recommended using marrubium vulgare (white horehound) extract to treat agricultural pests, and Marcus Terentius Varro suggested using amurca, seeped from olive oil presses, to protect seeds against ants, moles, and weeds (Smith & Secoy, 1975; Taylor, Holley, & Kirk, 2007). However, two major events in Europe pushed toward the discovery of effective pest control agents: the destruction of potato crops by late blight in Ireland in 1845–1848, followed by a famine that killed millions, and the destruction of the French vineyards caused by downy mildew, imported from America in 1878, that subsequently spread all over Europe. In 1882, Pierre-Marie-Alexis Millardet, professor of botanics at the University of Bordeaux, made the serendipitous discovery of the fungicide properties of sulfur and copper and created the mixture known as the “Bordeaux Mixture,” still used to treat mildew in vineyards and other crops (Fishel, 2013; Taylor et al., 2007).

In 1873, Othmar Zeidler, an Austrian chemist, synthesized DDT (dichlorodiphenyltrichloroethane). Its insecticide properties were discovered much later by the Swiss chemist, Paul Hermann Müller, who was awarded the Nobel Prize for Physiology and Medicine in 1948 for the effectiveness of DDT in fighting typhus and vector-borne diseases. In subsequent years, the development of resistance against DDT and the progress of the chemical industry prompted further research into new weapons against insects as well as weeds. The carbamate and organophosphate pesticides and the phenoxy acid herbicides appeared on the market, and their use became widespread worldwide. As a result, crop production could be substantially increased, improved, and better preserved in a cheap and effective fashion.

Definition

According to the U.S. Environmental Protection Agency (US EPA) definition, a pesticide is “any substance or mixture of substances intended for preventing, destroying, repelling, regulating, or controlling pests” (U.S. EPA, 1975), which include any unwanted organisms, from insects to rodents to weeds, that affect crops, livestock, foodstuffs, or human health, or damage any human activity or man-made infrastructure. The definition of pesticide covers about 100,000 different chemicals, inorganic and organic, that are grouped according to their function (e.g., insecticides, herbicides, fungicides, fumigants, rodenticides, fertilizers, growth regulators, etc. against specific pests such as snails or human parasites) or their chemical structure (organochlorines, organophosphates, pyrethroids, carbamates, dithiocarbamates, organotin compounds, phthalimides, phenoxy acids, heterocyclic azole compounds, coumarins, etc.). Using chemical agents with different structures is important to prevent insects and fungi from developing resistance, which is the reason why different treatment protocols are applied to different crops, or to the same crop in different seasons, or in different parts of the world. Along with the multiple crops and/or livestock to be treated each season on each farm, the strategy of changing patterns contributes to making it particularly difficult to link nondeterministic effects showing up after a long latency to any specific chemicals. Other conditions contributing to make the assessment of occupational exposure to pesticides especially complex include the multiple routes of absorption, such as inhalation during spraying, and dermal contact. Dermal absorption may occur because of carelessness with wearing personal protective equipment in greenhouses and outdoors, or in its proper dismissal/disposal, and/or poor personal hygiene, and/or contact with the plants when re-entering too soon the treated area, not respecting the due re-entry time. Moreover, the exposure pattern is also complicated by the changing weather conditions in outdoor spraying. For these reasons, studies of pest control workers using specific chemicals for public health purposes, or agricultural extension agency workers taking accurate notes of treatments applied, are mostly informative.

The Pesticide Market

In the last decade, pesticide sales have been roughly stable worldwide with an overall budget of $40 billion, with the U.S. market accounting for 31.6% of the total (Grube, Donaldson, Kiely, & Wu, 2011). In the last decade, the most significant increase in demand for pesticides has occurred in Central and South America (6.7% annual increase from 2004 to 2014), followed by the Asian market (4% annual increase from 2004 to 2014); the latter is the second largest after North America. Even the small African market, accounting for 3.5% of the global pesticide expenditure in 2004, has shown a sharp 6.4% annual increase in the same period. An annual increase has also been observed in Europe, although less pronounced. Overall and for agricultural uses, the herbicides predominate over the insecticides and fungicides, while household use of insecticides accounts for a larger share than agricultural use, equaling the amount of nonagricultural use of herbicides (Seedquest, 2016). Nonagricultural uses of pesticide include primarily weeds, insects, and other pest control in the household and its premises, parks and golf courses, as well as for public health applications (e.g., mosquito control) and weed control along roads, railroads, and in commercial and industrial areas (Grube et al., 2011). From 2001 to 2007, the two best-selling active ingredients in the U.S. agricultural market were the herbicides glyphosate and atrazine, with another four herbicides and four fumigants (including methyl bromide), ranking among the first 10 active ingredients; chlorpyrifos, the first insecticide, ranked 14 (Grube et al., 2011).

Pesticides in the Environment

Pesticides spread to the environment from specific points of release, such as manufacturing plants, mixing-and-loading facilities, spills, sewage treatment plants, and wastewater and solid waste disposal sites, and from diffuse nonpoint sources, including runoff from agricultural and urban land. Runoff from agricultural and urban land, and rain precipitation and dry deposition from the atmosphere, can transport pesticides to streams and groundwater (Figure 1). For instance, the annual transport to streams of atrazine, a commonly used herbicide, accounts approximately for 1% of the amount applied to their watershed (U.S. Geological Survey, 2006). Chemical and biological reactions in the ground, the atmosphere, and water transform pesticides to new compounds, which may or may not contain the same or new toxicological properties, with a half-life specific for each individual chemical. Depending on their chemical-physical properties, pesticides and their transformed and bio-transformed byproducts drift through the atmosphere and/or move through streams and groundwater to substantial distance from their original point source. The atmospheric drift of long-lived organochlorines, such as chlordane, DDT, and dieldrin, toward remote geographical areas where they were never used, along with their prolonged bio-persistence and accumulation through the food chain, is thought to explain the global burden and their fat content in Arctic mammals (Majewski & Capel, 1995; U.S. Geological Survey, 2006).

Pesticides and Human HealthClick to view larger

Figure 1. Distribution of pesticides in the environment. (Modified from U.S. Geological Survey, 2006.)

Exposure to pesticides may occur in the chemical industry, at the manufacturing stage, and in the application in open agricultural fields, but also in greenhouses, warehouses, stables, and in urban and rural environments for public health purposes. Insecticides, fungicides, and rodenticides can be used in libraries and archives to preserve the document collections for future use by humankind. Insects and mold can destroy printed pages, bindings, covers, and valuable documents or damage them with staining. Molds can act particularly quickly after flooding or due to faulty air-handling systems generating high-humidity conditions. Public meeting places (e.g., movie theaters, shopping malls, restaurants, and any commercial activity) also require a pest-free environment; mice, cockroaches, and other insects generate fear and anxiety in the staff and the public, and they can contaminate the food preparation process or make the ambient air unpleasantly smelly or a vehicle of microbial diseases. Herbicides are also extensively used to destroy weeds along railway tracks or highways. Finally, the general public can be exposed to the pesticide residues in the feedstock or through contaminated water.

With regard to the chemical industry, several serious accidents have occurred in different parts of the world. These include Bophal, India, in 1986 in a plant producing carbaryl; Seveso, Italy, in 1976; and Ludwigshafen, Germany, in 1953 in phenoxy herbicide manufacturing plants. These industrial accidents have contributed to public anxiety toward chemical plants, in general, and pesticide manufacturing and use in particular. Inappropriate disposal or use of pesticides has contributed by causing community poisonings, such as the dioxin contamination episode from landfills in the Quail Run Mobile Manor in Gray Summit, Missouri, in 1983, or the use of hexachlorobenzene as a grain fungicide in Turkey in 1955–1959 contaminating bread and causing about 4,000 poisonings and 500 deaths. Also, the easy availability of poorly regulated toxic pesticides in developing countries makes them popular for suicidal uses (Eddleston et al., 2002).

The relevance of such global contamination to human health depends on its geographic extent, the dietary intake through contaminated foodstuffs, the age segment of the affected population, and the often unpredictable interactions with other environmental contaminants. Exposure to pesticides in pregnant women might have detrimental effects, depending on the specific chemical and the specific phase of the pregnancy, with congenital malformations and growth retardation possible during the organogenesis period (22–50 days since fertilization), and central nervous system effects arising in the subsequent days up to delivery (The European Commission, 2002). Children are mostly sensitive to toxic pesticides, as their organs keep developing quickly after birth, as are the elderly, because of slower metabolism and easier skin absorption. The prevalence of unfavorable metabolic gene polymorphism in the target population also has a significant impact on the number of those affected. However, unless as a consequence of serious industrial accidents, exposure from environmental sources is usually orders of magnitude lower than that occurring in the workplace. Yet, low-level lifetime exposure in vulnerable populations cannot be discarded. For instance, an increased risk on non-Hodgkin lymphoma has been observed in association with concentration of several organochlorines in household carpet dust (Colt et al., 2006), and an elevated risk of infant acute leukemia was reported following maternal exposure to household carbamate insecticides when carrying rearrangements in the MLL gene (Alexander et al., 2001).

Important resources mapping out pesticide uses in the croplands have been developed, such the Web-based Pesticide National Synthesis Project of the U.S. Geological Survey (USGS) of the U.S. Department of the Interior that maps the estimated amount of 482 pesticides used since 1992 at the county level (U.S. Geological Survey, 2016). Such “big data” resources are of major importance, particularly when it becomes possible to cross-link this information with health registries to timely detect time-space variations in disease occurrence.

Toxicology of Pesticides

Toxicological Classification and Labeling of Pesticides

In recent years, the United Nations Economic Commission for Europe (UNECE) Globally Harmonized System (GHS) has replaced the toxicological classification and labeling of chemical products (UNECE, 2009) by providing a basis for harmonizing regulations at the national, regional, and worldwide level to “enhance the protection of human health and the environment during the handling, transport and use of these chemicals.” The GHS classification is based on the acute effects, defined by the lethal dose (by ingestion) or lethal concentration (by inhalation) for 50% of experimental animals (DL50 or CL50, respectively), expressed by mg/kg body weight or mg/liter. Based on the DL50 or CL50, four classes of acute toxicity are defined (Table 1), each represented by a specific pictogram. The GHS classification is currently implemented in 67 world countries, including most European countries and the United States.

Table 1. Classification of Acute Toxicity According to the Global Harmonized System, UNECE, 2009

Hazard Class

Oral LD50 (mg/kg)

Skin LD50 (mg/kg)

Inhalation LC50 (mg/l)

Vapor/gas

Dust

1

≤ 5

≤ 50

≤ 0.5

≤ 0.05

2

50–300

50–200

0.5–2

0.05–0.5

3

300–2000

200–1000

2–10

0.5–1

4

2000–5000

1000–2000

10–20

1–5

Source: UNECE, 2009.

Based on the GHS criteria, the World Health Organization (WHO) International Program on Chemical Safety (IPCS) has reviewed its classification of selected pesticides by hazard (WHO, 2010). As a result, a few of the most hazardous pesticides have been moved between classes, taking into account severe health hazards not just acute toxicity (Table 2). The classification of active compound of selected pesticides is based on the acute oral and dermal LD50 to the rat; the most restrictive category is assigned in the case of discordance between the two values as well as adjusting by the acute human health effects not accounted for by LD50 assessments. In the case of formulations including two or more active ingredients, the manufacturer should apply the correct toxicological data. In the case of missing information from the manufacturer, the classification of a given formulation is defined by proportionally applying the respective LD50 to each ingredient according to the formula:

Σ LD50active ingredient%active ingredient in formulation×100

Table 2. WHO IPCS Classification Scheme for Pesticides, Based on the LD50 for the Rat (mg/kg Body Weight)

Hazard class

Oral

Dermal

Solids

Liquids

Solids

Liquids

Ia. extremely hazardous

≤5

≤20

≤10

≤40

Ib. highly hazardous

5–50

20–200

10–100

40–400

II. moderately hazardous

50–500

200–2000

100–1000

400–4000

III. slightly hazardous

>500

>2000

>1000

>4000

Tables 3 and 4 show the active compounds used as pesticides in each of the four IPCS hazard classes, along with additional information on the chemical type, main uses, GHS classification, and LD50 in the rat. As the LD50 in the rat is taken as the reference, compounds used as rodenticide might be expected to be included among the upper hazard classes; however, their actual use is primarily for public health purposes, therefore, they are not listed in Tables 3 and 4. Compounds used against specific pests (e.g., mites, lice, and nematodes) are included among the insecticides.

Table 3. Pesticides Currently Used for Agricultural Purposes Listed in the IPCS Hazard Class Ia (Extremely Hazardous)

Common name

CAS no.

Chemical type

Physical state

GHS hazard class

LD50 (mg/kg)

Insecticides

Aldicarb

116-06-3

Carbamate

Solid

1

0.93

Chlorethoxyfos

54593-83-8

Organophosphate

Liquid

1

1.8

Chlormephos

24934-91-6

Organophosphate

Liquid

2

7.0

Disulfoton

298-04-4

Organophosphate

Liquid

1

2.6

EPN (O-ethyl O-(4-nitrophenyl) phenylphosphonothioate)

2104-64-5

Organophosphate

Solid

2

14.0

Ethoprophos

2104-64-5

Organophosphate

Liquid

2

Dermal 26.0

Mevinphos

26718-65-0

Organophosphate

Liquid

1

Dermal 4.0

Parathion

56-38-2

Organophosphate

Liquid

2

13.0

Parathion-methyl

298-00-0

Organophosphate

Liquid

2

14.0

Phorate

298-02-2

Organophosphate

Liquid

1

2.0

Phosphamidon

13171-21-6

Organophosphate

Liquid

2

7.0

Sulfotep

3689-24-5

Organophosphate

Liquid

1

5.0

Tebupirimfos

96182-53-5

Organophosphate

Liquid

1

1.3

Terbufos

13071-79-9

Organophosphate

Liquid

1

2.0 (broad range)

Fungicides

Calcium cyanide

592-01-8

Inorganic

Solid

2

39.0

Captafol*,

2425-06-1

Phthalimide

Solid

5

5000.0

Hexachlorobenzene*,

118-74-1

Organochlorine

Solid

5

Dermal 10000.0

Mercury chloride

7487-94-7

Inorganic

Solid

1

1.0

Phenylmercury acetate

62-38-4

Organic mercury

Solid

2

24.0

(*) Captafol is an animal carcinogen (IARC Group 2A); hexachlorobenzene causes porphyria in humans and is included in the list of persistent organic pollutants, the use of which is restricted based on the Stockholm Convention as of May 17, 2004.

(**) Calcium cyanide yields cyanide gas by reacting with water.

(‡) Trade of captafol, hexachlorobenzene, mercury compounds, parathion, parathion-methyl, and phosphamidon is regulated by the Rotterdam Convention on prior informed consent as of February 24, 2004.

Table 4. Pesticides Currently Used for Agricultural Purposes Listed in the IPCS Hazard Class Ib (Highly Hazardous)

Common name

CAS no

Chemical type

Physical state

GHS hazard class

LD50 (mg/kg)

Insecticides

Azinphos-ethyl

2642-71-9

Organophosphate

Solid

2

12.0

Azinphos-methyl

86-50-0

Organophosphate

Solid

2

16.0

Butocarboxim

34681-10-2

Carbamate

Liquid

3

158.0

Butoxycarboxim

34681-23-7

Carbamate

Liquid

3

Dermal 288.0

Cadusafos

95465-99-9

Organophosphate

liquid

2

37.0

Calcium arsenate

7778-44-1

Inorganic

Solid

2

20.0

Carbofuran

1563-66-2

Carbamate

Solid

2

8.0

Chlorfenvinphos

470-90-6

Organophosphate

Liquid

2

31.0

Coumaphos

56-72-4

Organophosphate

Solid

2

7.1

Cyfluthrin

68359-37-5

Pyrethroid

Solid

2

15 (broad range)

Beta-cyfluthrin

68359-37-5

Pyrethroid

Solid

2

11 (broad range)

Zeta-cypermethrin

52315-07-8

Pyrethroid

Liquid

3

86 (broad range)

Demeton-S-methyl

919-86-8

Organophosphate

Liquid

2

40.0

Dichlorvos

62-37-7

Organophosphate

Liquid

3

56.0

Dicrotophos

141-66-2

Organophosphate

Liquid

2

22.0

4,6-Dinitro-o-cresol

534-52-1

Nitrophenol

Solid

2

25.0

Ethiofencarb

29973-13-5

Carbamate

Liquid

3

200.0

Famphur

52-85-7

Organophosphate

Solid

2

48.0

Fenamidophos

22224-92-6

Organophosphate

Solid

2

15.0

Flucytrinate

70124-77-5

Pyrethroid

Liquid

3

127.0 (broad range)

Formetanate

22259-30-9

Carbamate

Solid

2

21.0

Furathiocarb

65907-30-4

Carbamate

Liquid

2

42.0

Heptenophos

23560-59-0

Organophosphate

Liquid

3

96.0

Isoxathion

18854-04-8

Organophosphate

Liquid

3

112.0

Lead arsenate

7784-40-9

Inorganic

Solid

2

10.0 (broad range)

Mecarban

2595-54-2

Organophosphate

Oil

2

36.0

Methamidophos

10265-92-6

Organophosphate

Solid

2

30.0

Methidathion

950-37-8

Organophosphate

Liquid

2

25.0

Methiocarb

2032-65-7

Carbamate

Solid

2

20.0

Methomyl

16752-77-5

Carbamate

Solid

2

17.0

Monocrotophos

6923-22-4

Organophosphate

Solid

2

14

Omethoate

1113-02-6

Organophosphate

Liquid

2

50.0

Oxamyl

23135-22-0

Carbamate

Solid

2

6.0

Oxydemeton-methyl

301-12-2

Organophosphate

Liquid

3

65.0

Paris green (copper arsenate)

12002-03-8

Inorganic

Solid

2

22.0

Pentachlorophenol

87-86-5

Chlorophenol

Solid

2

Dermal 80.0

Propetamphos

31218-83-4

Organophosphate

Liquid

3

106.0

Tefluthrin

79538-32-2

Pyrethroid

Solid

2

22.0 (broad range)

Thiofanox

39196-18-4

Carbamate

Solid

2

8.0

Thiometon

640-15-3

Organophosphate

Oil

3

120.0

Triazophos

24017-47-8

Organophosphate

Liquid

3

82.0

Vamidothion

2275-23-2

Organophosphate

Liquid

3

103.0

Fungicides

Blasticidin-S

2079-00-7

Aminoacylnucleoside

Solid

2

16.0

Edifenphos

17109-49-8

Organophosphate

Liquid

3

150.0

Herbicides

Acrolein

107-02-8

Aldehyde

Liquid

2

29.0

Allyl alcohol

107-18-6

Alcohol

Liquid

3

64.0

DInoterb

1420-07-1

Nitrophenol

Solid

2

25.0

(*) Also used as a herbicide.

(‡) Trade of carbofuran, DNOC, methamidophos, monocrotophos, and pentachlorophenol is regulated by the Rotterdam Convention on prior informed consent as of February 24, 2004.

Overall, besides those listed in Tables 3 and 4, another 215 active compounds are listed in IPCS class II (moderately hazardous): 79 insecticides, including popular insecticides such as acephate, carbaryl, chlordane, chlorpyrifos, cypermethrin, DDT, diazinon, dimethoate, endosulfan, lindane, permethrin, and propoxur; 56 fungicides, such as copper sulfate and other copper salts, propiconazole, tebuconazole, thiram, triadimefon, and ziram; 70 herbicides, such as 2,4-D, dicamba, diclofop, diquat, molinate, and paraquat; and a few others with different designations (8 plant growth regulators, 2 bacteriostatics, 1 unspecified). IPCS class III (slightly hazardous) lists another 104 active compounds: among them are the two best-selling herbicides atrazine and glyphosate and one of the most popular organophospates, malathion. Finally, IPCS class IV (pesticides unlikely to present acute hazards in normal use) includes 179 compounds. Upgrades are expected given the recent International Agency for Research on Cancer (IARC) revision of carcinogenicity of lindane (Group 1), DDT, and glyphosate (Group 2A) and others. The IPCS tables also list 291 active compounds known to have been discontinued, based on information from the manufacturers and on the subsequent editions of the Pesticide Manual. Further information on specific compounds can be found at http://www.who.int/ipcs/.

Toxicological Mechanisms

Organochlorines

Organochlorine insecticides result from hydrocarbons, aromatic or aliphatic, covalently bonded to one or more chlorine atoms, replacing hydrogen atoms. DDT was the first of a group of chlorinated aromatic hydrocarbons, including hexachlorobenzene and methoxychlor, most of which have been banned because of their toxicity to humans and wildlife and their persistence in the environment. These compounds affect the ion transport through membranes; in the neuron membrane, the inhibition of ion transport slows or stops its repolarization following an impulse, resulting in hyperexcitability (Duffus & Worth, 2006). Cyclodienes (including the obsolete chlordane), aldrin, dieldrin, mirex, and the hexachlorocyclohexane isomers (including lindane and endosulfan) are all also discontinued; they act at the central nervous system level, as antagonists of the gamma-aminobutyric acid (GABA) neurotransmitter, which also affects neuronal repolarization, causing uncoordinated hyperexcitability (Duffus & Worth, 2006).

Due to their lipophilicity, the organochlorines are stored in body fat in a biologically inactive form, although they are extremely persistent, with a half-life for DDT reportedly within a 2- to 15-year range (Augustijn-Beckers, Hornsby, & Wauchope, 1994). This prolonged half-life is at once one of the major reason of concern for its environmental effects and one of the reasons for both the continuing effectiveness against malaria, yellow fever, typhus, and other vector-borne diseases and the relatively low cost of DDT.

In 1962, the biologist Rachel Carson published her influential book Silent Spring when DDT production was at its highest, with as much as 82 million kg/year being produced in the United States (Carson, 1962). In her book, and in several publications it inspired, adverse reproductive effects of organochlorine pesticides were described in fish and several avian species, including top predators, such as bald eagles, the American national bird. As a result of the growing public concern about its toxicity in wildlife, its widespread contamination, the increasing pest resistance, and the development of alternative insecticides, such as organophosphates, carbamates, and pyrethroids, DDT was banned in the early 1970s in numerous Western countries (U.S. Environmental Protection Agency, 1975). In 2001 the WHO Stockholm Convention on Persistent Organic Pollutants (POPs) made an exception to the worldwide ban on DDT production and use “for disease vector control in accordance with the World Health Organization recommendations and guidelines on the use of DDT and when locally safe, effective and affordable alternatives are not available . . .” In 2011, WHO declared its support for the indoor use of DDT in countries in which malaria is a health problem (World Health Organization, 2002).

Currently, DDT is off patent with only two plants (one in China and another apparently in North Korea) continuing its manufacture, and there are plenty of more expensive, less persistent, and less studied alternatives available from major chemical corporations; therefore, it is understandable why the debate on its complete ban in malaria-ravaged countries is still so controversial.

When administered orally, DDT has a low-to-moderate acute toxicity to mammals, which accounts for the delayed investigation on acute human health effects. These include nausea, diarrhea, increased liver enzyme activity, irritation of the eyes and upper airways, disturbed gait, malaise, and excitability. At high doses, tremors and convulsions are possible (Extoxnet, 2008). The other organochlorines share with DDT the acute neurologic effects, although only the cyclodienes (aldrin, dieldrin, endrin, endosulfan, and methoxychlor) mirex and lindane are capable of inducing severe seizures and fatalities. Induction of hepatic microsomal drug–metabolizing enzymes may also occur following exposure to DDT and cyclodienes, which would accelerate their own metabolism but also interfere with that of steroid hormones and therapeutic drugs. Other effects include myocardial irritability, which would predispose to cardiac arrhythmia, and porphyria cutanea tarda, which has been described as a consequence of ingestion of hexachlorobenzene-treated wheat (Roberts & Routt Reigart, 2013). Reproductive and neoplastic effects have also been reported, which will be discussed under the specific subheadings.

The organochlorines stored in body fat are at equilibrium with the serum, where they tend to mobilize in the blood with pregnancy, breastfeeding, aging, disease, or fasting. Use of serum or plasma concentration is nowadays the standard method of biomonitoring organochlorine body burden (rather than fat biopsy), because of lesser invasiveness and easier acceptability of the procedure.

Organophosphates

Organophosphates are esters of phosphoric acid, with an oxygen atom linked with a double bond to phosphorus, two lipophilic groups, and a halide also bonded to phosphorus. Organophosphates inhibit acetylcholinesterase (AChE), an enzyme located in the postsynaptic membrane that degrades acetylcholine (ACh) into choline and acetic acid. ACh is the neurotransmitter of cholinergic postsynaptic receptors, including the nicotinic receptors (located in the neuromuscular junction and the autonomic ganglia) and the muscarinic receptors (located in the central nervous system, and at the junction between the postganglionic neuron and the tissue innervated by the parasympathetic autonomic nervous system). By degrading ACh while linked to its postsynaptic membrane receptor, AChE interrupts nervous stimulation; AChE inhibition by organophosphorous compounds allows a prolonged bond between ACh and its receptor, resulting in respiratory paralysis and death of the insect.

The effects in mammals differ in relation to changes in the metabolic pathways. The phosphorus-oxygen (=P=O) active group of organophosphates covalently binds the serine hydroxyl group in the active site of AChE, the same linking ACh (Figure 2). In fact, several thiophosphate insecticides, such as parathion and malathion, have a sulfur atom linked to phosphorus, which is replaced by oxygen by an oxidase in its first metabolic step resulting in the active metabolite. Their toxic action is therefore delayed and they are less toxic to humans compared to other organophosphates such as mevinphos or monocrotophos (Brown, 1999).

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Figure 2. Chemical structures of acetylcholine and organophosphate.

Replacing the oxygen with more stable substitutes makes the bond between the organophosphate and AChE irreversible. Such properties have been used to manufacture chemical weapons such as nerve gases, including sarin and the VX agent.

Organophosphates are metabolized by carboxyl esterases, leading to separation of a leaving group from alkyl phosphates (APs), which are subsequently excreted with urine and can be used as a biomarker of dose (Sudakin & Stone, 2011). When the enzyme activity is reduced more than 50% of the background level (Legaspi & Zenz, 1994) following organophosphate poisoning, AChE inactivation causes ACh accumulation throughout the nervous system; this is responsible for the nicotinic (asthenia, muscle weakness, tremor initially at the upper and lower limbs, headache, cramps, mydriasis, tonic-clonic convulsions, and tachycardia) and muscarinic (nausea, vomit, diarrhea, hypotension, abdominal spasms, bronchospasm, lachrymation, and salivation) clinical effects, due to overstimulation of the respective receptors. Such symptoms might be preceded by cough, phlegm, and headache, thus simulating a trivial flu episode.

Organophosphates can enter the organism by inhalation, dermal contact, or ingestion, with the last mainly associated with suicidal purposes. Biological monitoring of exposure is therefore the preferred method of exposure surveillance to account for multiple possible sources of absorption. The measurement of AChE activity in serum is easily performed, but it does not exactly reflect the true AChE in the nervous system, although both are inhibited by organophosphates. Instead, AChE activity in red blood cells is a more reliable predictor of enzyme activity in the nervous system. Measurement of urinary AP excretion complements the measurement of cholinesterase activity as it reflects recent exposure, while AChE enzyme activity recovers slowly over time. However, the lack of reference values for AP and the other metabolites of organophosphorous pesticides prevents their practical application to biomonitoring exposure in occupational settings (Legaspi & Zenz, 1994). More recently, the detection of organophosphate-protein adducts with cholinesterase in the blood of exposed subjects has been proposed as a biomarker of exposure within weeks from first exposure (Thompson, Prins, & George, 2010).

Carbamates

Carbamates are a group of insecticides deriving from carbamic acid. Their mechanism of action also involves AChE inhibition through carbamylation, which, unlike with organophosphates, is reversible within a few hours, thus preventing its use as a biomarker (Legaspi & Zenz, 1994). As for organophosphates, exposure occurs by inhalation and skin contact, with ingestion involved mainly in suicidal attempts or incidents. Measuring the active molecule itself in the serum or urinary metabolites, such as 1-naphthol for carbaryl and phenol conjugates for propoxur and carbofuran, has been explored (Araoud, 2011), but not widely applied.

Carbamates are usually considered to be of limited acute toxicity. For this reason, carbaryl dust is used against fleas in pets and in typhus control public health programs. However, at high concentration, carbaryl can cause skin irritation and systemic intoxication. Aldicarb is listed in the IPCS group Ia of extremely hazardous pesticides in conditions of normal use, and several other commonly used carbamates, such as carbofuran and methomyl, are listed in the IPCS group Ib of highly toxic pesticides (see Table 4).

Dithiocarbamates

Dithiocarbamates act as metabolic inhibitors, and they are non-AChE inhibiting substances, generally of low toxicity, resulting from dithiocarbamic acid complexes with transition metals, such as zinc or manganese. Zineb, Maneb, Mancozeb, Thiram, and Ziram are among the most popular in this class of pesticides. These compounds are mainly used as fungicides and animal repellents in orchards and to protect harvested crops and seeds during storage and transportation, as well as in the treatment of human scabies, as sunscreens, and as bactericides incorporated into soap or directly applied to the skin (Extoxnet, 2008). Several dithiocarbamates can cause nausea, vomiting, and headache when consumed with alcohol, and for this reason disulfiram has been used in the treatment of alcoholics as a form of voluntary behavior modification. Thiram is an irritant for the upper airways and the conjunctiva, and acute exposure is followed by headaches, dizziness, fatigue, nausea, and diarrhea (Extoxnet, 2008); prolonged exposure can cause skin sensitization with contact dermatitis in the hands, forearms, and feet (Legaspi & Zenz, 1994). Rare cases of mild peripheral neuropathy have been reported following disulfiram treatment in alcoholics (Gessner & Gessner, 1992), and signs of poor coordination, abnormal deep tendon reflexes, and reduced muscular strength have been reported among Ecuadorian pesticide users, who were also exposed to organophosphates and carbamates (Cole, Carpio, Julian, & Leon, 1998). This might be an indirect effect, as the metabolic breakdown of dithiocarbamates can lead to formation of carbon disulfide (used in the past as a solvent in the rubber industry), a powerful neurotoxin of the peripheral nerves.

The urinary excretion of ethylenethiourea (ETU) is used as a biomarker of workplace exposure to dithiocarbamates, but also to monitor the dietary consumption of such chemicals as food contaminants in the general population. Because ETU inhibits the synthesis of thyroid hormones, high-level exposures to the parent fungicides can be associated with possible hypothyroidism, increased thyroid-stimulating hormone (TSH) secretion, and hypofunctional goiter (Colosio & Rubino, 2015).

Pyrethroids

Pyrethrum is a mixture of chemicals including six pyrethrins with active insecticidal properties naturally occurring in chrysanthemum flowers; the pyrethrins are known to have been used in Asia against ticks and various insects since the 19th century. Currently used pyrethroids are structurally similar to the pyrethrins, but they are chemically manufactured to be more active against insects and to last longer in the environment (Bradberry, Cage, Proudfoot & Vale, 2005). Type I carboxylic esters, such as permethrin, block the sodium channels in nerve membrane, thus causing repetitive and prolonged neuronal discharge, but not severe depolarization. Class II cyano esters, such as cypermethrine, cause more persistent membrane depolarization and eventually nerve blockade, resulting in respiratory paralysis in insects (Bradberry et al., 2005). Pyrethroids are rapidly metabolized in humans mostly through hydrolysis of the ester linkage and subsequent oxidation and/or conjugation. Others, such as allethrin, more resistant to hydrolysis, undergo direct oxidation (Miyamoto, 1976).

Effects in humans are mild because of lesser sodium channel sensitivity, greater body size and higher body temperature, and their rapid metabolism. Symptoms include numbness, paresthesias, and, following severe type II poisoning, seizures due to the blockade of the GABA-gated chloride channels. Dermal absorption is the main route with occupational exposure; inhalation exposure is increasing in importance when pyrethroids are used in confined spaces. Despite their extensive use worldwide, including as household insecticides, severe human poisoning has seldom been reported (Bradberry et al., 2005). Pyrethroid metabolites, such as 3-phenoxybenzoic acid (3-PBA), trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (trans-DCCA), 4-fluoro-3-phenoxybenzoic acid, and cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid, can be monitored in the urine using high-performance liquid chromatography coupled with mass spectrometry (HPLC/MS/MS) (McKelvey et al., 2013)[35].

Chlorophenoxyacetic Acids

Chlorophenoxyacetic acids include several chemicals functionally related to the natural growth hormone indole acetic acid (IAA), that act selectively on broadleaf plants, by inducing a rapid, uncontrolled growth, followed by death, while preserving crops. 2,4-Dichlorophenoxyactic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) were synthesized in 1941, and methylchlorophenoxyacetic acid (MCPA) was introduced in the market in 1945 (IARC, 1986). Use of 2,4,5-T was discontinued in the United States and numerous other countries in the early 1970s, as inherently contaminated with the 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD); 2,4-D was a major (50%) component of the Agent Orange defoliant used during the Vietnam War, as well as 2,4,5-T contaminated by TCDD.

Episodes of poisoning among workers and the general population and environmental contamination with dioxin, due to accidents in 2,4,5-T manufacturing plants, have occurred in Germany and in Italy (Schechter, 1994). More recently, manufactured 2,4-D technical acids have been used in crops, pasture and rangeland, forest management, home and garden, and for the control of aquatic vegetation; these are free of dioxin contamination, but 2,4-D amine and ester products may contain TCDD in amounts ranging from 5 to 500 ppb (Extoxnet, 2008). Other widely used phenoxy herbicides include MCPA, not manufactured in the United States, mecoprop, and dichlorprop. Fenoprop, known as Silvex in the United States, was banned in 1985 (U.S. Environmental Protection Agency, 2016).

Phenoxy herbicide can be readily absorbed by inhalation, skin contact, and ingestion and is excreted in urine mostly unchanged within various time lags depending on the individual compound, with half-lives ranging from 10 to 20 hours for 2,4-D, less than 24 hours for 2,4,5-T and MCPA, and somewhat longer for Silvex, dichlorprop, and mecoprop (IARC, 1986). Plasma and urinary levels of the unmodified phenoxy acids can be used for exposure biomonitoring (Legaspi & Zenz, 1994). There is no evidence of accumulation of phenoxy acids in human tissues. With a 375–666 mg/kg LD50 in the rat, 2,4-D is classified as moderately hazardous because of producing eye and skin irritation among agricultural workers. Fatigue, nausea, and rare instances of peripheral nerve effects have been described following high-level exposures. Prolonged inhalation can also cause cough, dizziness, and temporary lack of muscle coordination. Nonfatal intoxications with 2,4-D, mostly due to suicidal attempts or ingestion incidents, have resulted in acute parasympathetic symptoms and persistent neurological dysfunction. No long-term consequences were observed in a surviving case of MCPA poisoning (Extoxnet, 2008; IARC, 1986).

Other Pesticides of Common Use

Atrazine

Atrazine is a triazine herbicide used in agricultural crops, including sugarcane, corn, pineapples, rice, and on evergreen tree farms and forests, before and after crop emergence, and against weed growth in highways and railroads, in the spring and summer months (Extoxnet, 2008). Although banned in Europe in 2004 because of groundwater contamination, in the United States it is still the second most widely used herbicide after glyphosate. It can enter the body through inhalation, ingestion or skin contact. It is listed among the slightly hazardous pesticides (IPCS class III), although it can cause skin rashes, irritation of conjunctiva and mucous membranes, abdominal pain, diarrhea, and vomiting. Several episodes of lethal food poisoning caused by atrazine have been described. About two thirds of the ingested dose is eliminated in the urine within 72 hours, while a 15% residue is retained, mainly in the liver, kidneys, and lungs (Hayes & Laws, 1990). Glutathione conjugation is the major route of biotransformation, resulting in atrazine mercapturate and N-dealkylation; urinary concentrations of these metabolites reflect recent exposure.

Glyphosate

Glyphosate is the technical name of N-(phosphonomethyl)glycine, initially synthesized for medical applications, but with herbicide properties discovered in 1970 (IARC, 2015). It is an acid, formulated as a salt with isopropylamine, ammonium, or sodium in commercial preparations. As it contains a phosphatidyl functional group, it is commonly considered as an organophosphate, but it is not an organophosphate ester and it does not significantly inhibit cholinesterase activity (Weed Science Society of America, 1994). Because of its structural resemblance to phosphoenol pyruvate, once absorbed by the plant, glyphosate inhibits enolpyruvyl-shikimate-3-phosphate synthase (EPSPS); this enzyme converts the end products of glycolysis and the pentose phosphate pathway to 5-enolpyruvyl-shikimate-3-phosphate (ESP), a precursor for aromatic amino acids, hormones, vitamins and other essential plant metabolites (Glyphosate Task Force, 2013).

Glyphosate is the best-selling herbicide worldwide, for the control of annual and perennial plants including grasses, sedges, broadleaved weeds, and woody plants; it can be used on noncropland as well as on a great variety of crops (Extoxnet, 2008). Experimental studies have not shown significant signs of acute or chronic toxicity, reproductive or mutagenic effects, and therefore it is included in IPCS class III (slightly hazardous). However, IARC has recently evaluated the evidence for human carcinogenicity of glyphosate and classified it in the Group 2A as a “probable human carcinogen,” because of limited evidence of an association with risk of non-Hodgkin’s lymphoma in human studies and sufficient evidence of carcinogenicity in experimental animals (Cole et al., 1998). A few clinical reports of rhabdomyolysis among persons exposed to organophosphates and specifically to glyphosate have been published, and the IPCS states that “rhabdomyolysis is a well known consequence of serious intoxications, and it shows up with relative frequency in association with serious intoxications by organophosphates” (IPCS INCHEM, 1998); however, the association has not been tested with formal epidemiologic studies to date. Glyphosate is poorly absorbed from the digestive tract and is largely excreted unchanged by mammals (Miyamoto, 1976); urinary excretion can be by monitored with HPLC, with post-column reaction and fluorescence detection, in occupationally and environmentally exposed population groups (Acquavella et al., 2004).

Paraquat

Paraquat (N,N′-dimethyl-4,4′-bipyridinium dichloride) is a quaternary nitrogen herbicide used for broadleaf weed control, as a crop desiccant and defoliant, and as an aquatic herbicide in numerous countries, while it is regulated in the United States for use by certified applicators only (Extoxnet, 2008). According to the IPCS classification (see below), Paraquat is moderately hazardous (class II); however, a few instances of accidental or suicidal ingestion have been described, with the lung as the target organ of paraquat toxicity, resulting in a typical pulmonary fibrosis (“paraquat lung”) and death from respiratory failure. The lethal dose in humans is 35 mg/kg. Kidney is another target organ of paraquat toxicity; accidental or suicidal ingestion of very high doses has resulted in acute kidney failure due to proximal tubular dysfunction, similar to observations in experimental animals (Legaspi & Zenz, 1994).

Paraquat accumulates in the lung tissue where it is reduced to an unstable free radical by a NADPH-dependent microsomal flavoprotein reductase and subsequently re-oxidized to produce a superoxide anion. Lung toxicity results from cell death by lipid peroxidation or NADPH depletion (Smith, 1987). Skin absorption is normally less important, and it is not followed by systemic toxicity. However, prolonged contact can result in necrosis, white spots, and/or cracking of nails; if extensive skin damage occurs, paraquat can be absorbed and systemic toxicity becomes more likely (Bismuth, Hall & Wong, 1995). Paraquat can be measured in urine samples by enzyme-linked immunosorbent assay (ELISA), a useful workplace exposure biomarker (Park et al., 2008).

Azole Fungicides

Azoles are a group of heterocyclic compounds with a 5-atom ring, including two carbon and three nitrogen atoms, which differentiate by the relative position and the hydrogen bond of nitrogen atoms. They include two major groups, imidazoles (such as thiophanate methyl) and triazoles (such as propiconazole, tebuconazole, and triadimefon); these chemicals are widely used in a number of crops (vegetables, banana, apples, plums, papaya, grapes, citrus fruit, ornamental plants, wheat) as protective agents against fungi. Several azoles, such as ketoconazole and fluconazole, are also used to treat fungal infections in humans (Colosio & Rubino, 2015).

Azoles act by inhibiting lanosterol-14α‎-demethylase (CYP51), the main component of fungal membranes. However, other P-450 enzymes, including aromatase (CYP19), which is implicated in the transformation of testosterone and androstenedione to estradiol and estrone, respectively, are also inhibited by azole compounds. Also, CYP51 is highly expressed in male germ cells in early stages of their development, and its inhibition, together with CYP19 inhibition in humans, might result in endocrine disruption (Zarn, Bruschweiler, & Schlatter, 2003).

Inhalation of the azoles can cause irritation of the upper airways and the lungs. Azoles can be easily absorbed by dermal contact or ingestion; the unchanged compound is eliminated in the urine and feces in a few days, although a small amount undergoes biotransformation in the liver by oxidation (CYP3A4). The conjugated metabolites, such as triazolylalanine, triazolylacetic acid, and triazolylpyruvic acid, are common metabolites of triazole fungicides and can be detected in the urine (U.S. Environmental Protection Agency, 2008).

Methyl Bromide

Methyl bromide is the most widely used fumigant (a substance that produces a gas, vapor, fume, or smoke with a wide spectrum of biocide effects) (Legaspi & Zenz, 1994). Fumigants are applied on the soils, prior to sowing, to sterilize them particularly against fungi spores, but their main use is to protect grains, cereals, flour, nuts, and rice in interior buildings (such as warehouses and storage rooms). Methyl bromide, in particular, also has insecticide and rodenticide properties, and therefore it is also used to treat railroad cars or buildings.

Other fumigants include ethylene dibromide, ethylene dichloride, dichlorobenzene, sulfur dioxide, carbon disulfide, hydrogen cyanide, and calcium cyanide. Several of these chemicals (including methyl bromide, ethylene dichloride, and hydrogen cyanide) are highly toxic, but they are not classified by IPCS, although threshold limit values (TLVs) for occupational exposures have been adopted in several countries. The methyl bromide TLV is 5 ppm; it is denser than air, so that it can form clouds in low ventilated areas where it concentrates.

Human exposure to methyl bromide can occur during its use or when entering treated buildings without proper personal protective equipment. Main routes of absorption are inhalation and dermal contact. Because methyl bromide is a strong irritant, it can cause a severe vesicular dermatitis particularly in moist skin area, such as axillae, groin, and abdomen; by inhalation exposure, methyl bromide can cause pulmonary edema, with tremors and convulsions, dizziness, frequently with a delayed onset. Chronic exposure can lead to a peripheral neuropathy, vision and hearing disturbances, central nervous system effects (e.g., confusion, depression, euphoria, hallucination, irritability, and mood changes), and tubular kidney damage. In the cells, methyl bromide inactivates several enzymes, particularly hexokinases and pyruvate kinases, by methylation of their SH groups, thus interfering with pyruvate metabolism (Pillay, 2013).

Once inhaled, a portion of the methyl bromide is eliminated unchanged in the exhaled air, but a more substantial amount is decomposed into a bromide ion and methanol, subsequently detected in blood and urine. The half-life of plasma bromide is about 12 days, which accounts for its delayed and prolonged health effects (Extoxnet, 2008). Although plasma bromide measurement has been used to identify the agent following workplace intoxication, its use for routine monitoring of occupational exposure is not suggested (Legaspi & Zenz, 1994).

Health Effects of Pesticides

Asthma and Other Respiratory Effects

The occurrence of respiratory symptoms, impaired respiratory function, asthma, and chronic bronchitis among agricultural workers exposed to pesticides has been investigated in cross-sectional and longitudinal studies (Mamane, Baldi, Tessier, Raherison, & Bouvier, 2015). A review of the literature reported that, among cross-sectional studies, most studies of respiratory symptoms (12/15), and all studies of asthma (N = 4), respiratory function (N = 4), and chronic bronchitis (N = 3), found an association with occupational exposure to pesticides. Both obstructive and restrictive ventilatory impairments were reported, depending on what chemical class of pesticide was involved. Results from longitudinal studies were less consistent for asthmatic symptoms, while a positive association for chronic bronchitis was consistently reported in three studies. An elevated risk of chronic obstructive pulmonary disease and airways obstruction was also observed in pesticide production workers (Mamane et al., 2015). Most studies were unable to identify the specific chemical agent responsible for the observed associations. However, risk of wheeze, detected by questionnaire in a cross-sectional study, was moderately elevated (12–50%) among applicators of the herbicides, paraquat, S-ethyl-dipropylthiocarbamate (EPTC), and atrazine, and the organophosphate insecticides parathion, malathion, and chlorpyrifos (Hoppin, Umbach, London, Alavanja, & Sandler, 2002). Among pesticide applicators, significant associations with wheezing were also reported for the organophosphates dichlorvos and phorate and the herbicide chlorimuron-ethyl (Hoppin, London, Linch, & Alavanja, 2006). An association with the exacerbation of atopic asthma was noted for the herbicide pendimethalin and the carbamate insecticide aldicarb (Henneberger et al., 2013).

Also, atopic asthma was reported more frequently with exposure to seven insecticides, two herbicides, and one fungicide among farmers participating in the U.S. Agricultural Health Study. Risks were mostly elevated for both genders of agricultural workers with parathion and coumaphos, but only for women with metalaxyl and only for men with heptachlor, ethylene dibromide, and carbon disulfide. Pesticides associated with an increased risk of nonatopic asthma were permethrin among women and DDT, malathion, and phorate among men (Hoppin et al., 2008, 2009).

Immunotoxicity

Different groups of pesticides, including organophosphates and organochlorines, can affect numerous steps of the immune response (Li, 2007). For instance, several organophosphates can inhibit natural killer (NK) cell, lymphokine-activated killer (LAK) cell, and cytotoxic T lymphocytes (CTL) activity both in human and in animal studies, which would result in a reduced cellular immunity. T-cell subsets are also affected with a decrease in CD5 cells and, to a lesser extent, in CD4 cells; an increase in CD26 cells; and a moderate decrease in IL-2 production. Macrophages increase in size and phagocytic capability in mice. The humoral response is also affected, with a reduction in antibody production and in neutrophil function and an increase in autoantibodies; the Th1/Th2 cytokine balance is also disrupted, with a mild decrease in the count of CD4 T-helper lymphocytes (Li, 2007). The overall result is a mild immunosuppression.

The mechanisms of organophosphate immunotoxicity include: impairment of the granule exocytosis pathway and the FasL/Fas pathway of NK cells, LAK cells, and CTLs; induction of apoptosis and inhibition of serine hydrolases or other esterases of immune cells; and other yet to be completely elucidated pathways. Carbamates also share some of these immunotoxic effects (Corsini, Sokooti, Galli, Moretto, & Colosio, 2013). Consistent evidence is reported on the immunosuppressive effects of chlorinated compounds, such as pentachlorophenol and hexachlorobenzene. There is evidence for DDT in rodent studies, while human data are scanty, with some suggestion of an inverse correlation between plasma DDE body levels and IgA levels (Corsini et al., 2013). Chlordane seems associated with aberrant peripheral T-cell and B-cell regulation and autoimmunity approximately 10 years after exposure (Corsini et al., 2013). Infants exposed in utero to organochlorines may be more susceptible to their immunosuppressive effects, including a low white blood cell count, particularly lymphocytes, associated with depressed TNF‎α‎ and IL-10 secretion. On the other hand, dithiocabamates, such as mancozeb, appear to act as immunomodulators and to enhance the immune response; thus, they have been proposed as therapeutic agents and T-cell-specific stimulants against immunodeficiency conditions in adulthood (Corsini et al., 2013).

Endocrine Disruption

An endocrine disrupter is defined as an “exogenous substance or mixture that can alter functions of the endocrine system and consequently causes adverse effects in an intact organism or its progeny or in a subpopulation” (WHO International Program on Chemical Safety, 2002). Concern over potential endocrine disrupting effects of pesticides arose following the experimental finding that organochlorines (particularly DDT isomers and their DDE derivatives) and atrazine bind in vitro to the rat androgen receptor, thus significantly inhibiting the specific binding of [3H]5 α‎-dihydroxytestosterone (DHT) (Kelce et al., 1995). Various organochlorines also compete in vitro with β‎-estradiol in linking with the rat estrogen receptor and with the progesterone receptor and the estrogen receptor in alligators (Danzo, 1997; Vonier, Crain, McLachlan, Guillette, & Arnold, 1996). The response of estrogen responsive mammary rat tumor cells to o,p’-DDT (a less prevalent DDT isomer present as a contaminant in technical grade DDT) mimics that elicited by the natural estrogen 17β‎-estradiol (Robison, Sirbasku, & Stancel, 1985); the extent of the response in vitro varies between 70% and 100%, although delayed, and it links to the 8-9S estrogen-binding protein of rat testicular cytosol. In fact, the o,p’-DDT estrogen-inducible protein is indistinguishable from that formed after 17β‎-estradiol. Methoxychlor and β‎-HCH, at blood concentrations in the µg/L range, were associated with increased uterine and vaginal epithelial thickness compared to control animals ( Ulrich, Caperell-Grant, Jung, Hites, & Bigsby, 2000); similar to o,p-DDT, these compounds have affected the rate male sexual behavior in adulthood when administered during pregnancy (Vom Saal et al., 1995).

A valuable tool to assess human fertility is to calculate the “time to pregnancy” (TTP) index (i.e., the time before achieving pregnancy with unprotected intercourse (Joffe, 1997)) in relation to pesticide exposure. The analysis is frequently conducted using a modified Cox’s proportional hazard model, cutting the count of events at 12 months, which corresponds to the medical diagnosis of infertility. In this analysis, the hazard ratio between the time-related success in achieving pregnancy in the exposed versus the unexposed group is defined as the fecundability ratio. The exposure of Dutch fruit growers to the fungicide captan was associated with a significant reduction in the fecundability ratio (De Cock, Westveer, Heederik, Te Velde, & Van Kooij, 1994). Dibromochloropropane (DBCP) is another fungicide capable of significantly interfering with human reproduction; it was mostly used as an insecticide in banana plantations, causing azoospermia and oligospermia in the male workers in DBCP- manufacturing plants (Whorton, Millby, Krauss, & Stubbs, 1979) and a decrease in fertility (including sterility) among male Costa Rican banana plantation workers (Potashnik & Porath, 1995).

Although there are claims that DDT is responsible for the worldwide decline in sperm counts, it has not been shown to contribute to an impairment of male human fertility among highly exposed pest control applicators or among the general population (Campagna, Satta, Fadda, Pili, & Cocco, 2015; Cocco, Fadda, & Melis, 2006). Other pesticides for which a reduced human fecundability has been reported include dicamba, 2,4-D, dimethoate, and glyphosate (Cocco, 2002).

Other outcomes indirectly related to human fertility have been investigated in relation to pesticide exposure, including sperm count, sex hormone levels (e.g., plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone, and serum hormone-binding globulin (SHBG) levels), spontaneous abortion, and the male:female ratio at birth (Cocco, 2002) [76]. Table 5 provides a summary overview of the pesticides that have been tested for their endocrine disrupting potential. Overall, apart from specific exceptions, human studies demonstrating endocrine-disrupting effects are infrequent, and when they are available, the results seem inconsistent. A possible explanation for the inconsistent findings might be the effect of interindividual variations in response due to polymorphisms of metabolizing genes, such as cytochrome P4502E1, the glutathione S-transferases m and q, and the paraoxonase genes (Au, Sierra-Torres, Cajas-Salazar, Shipp, & Legator, 1999).

Table 5. Summary Evaluation of Pesticides with Endocrine-Disrupting Potential

Pesticide

In vitro studies

Animal studies

Human studies

UK-DE group*

Current uses

Organochlorines

Acetochlor

Thyroid inhibitor

Herbicide in corn crops

Alachlor

Antiestrogen

No reproductive effects in adult rats

Herbicide in corn crops, and aPR binding in adult rats soybeans, peanuts, dry beans/peas, grain sorghum, and sunflowers Banned in the EU

Aldrin

Weak estrogen, anti-androgen

Insecticide used up to 1970s

Chlordane and oxychlordane

Weak estrogen and anti-androgen

Reduced fertility in rats

Insecticide, termite control Banned in the United States

Chlordecone (kepone)

Weak estrogen competitive aPR binding

Reduced fertility

Reduction in sperm quality

Insecticide (tobacco, citrus trees, ornamental shrubs, bananas, ant & roach traps) Banned by the Stockholm convention

DDT congeners

Anti-androgen, estrogen

Estrogenic effects

No evidence from population studies

Insecticide for Public Health purposes only

o,p′-DDE o,p′-DDE

Estrogen

Thyroid inhibition

Minor DDT derivative

p,p′-DDEp,p′-DDE

Anti-androgen

Major DDT derivative

Dicofol

Weak estrogen and anti-androgen

Mite control

Dieldrin

Weak estrogen, weak anti-androgen

No reproductive effects

Insecticide (corn and cotton crops)

Endosulfan

Weak estrogen Competitive aER and aPR binding Impaired steroid synthesis in Leydig cells

Damage to seminiferous tubules in male rats and reproductive organs in female mice

Insecticide (fruits, grains, tea, vegetables, tobacco, and cotton). Banned by the Stockholm convention

Endrin

Weak estrogen and anti-androgen

Insecticide Banned in many countries

Fenarimol

Weak estrogen and anti-androgen

Insecticide

Heptachlor

Reduced fertility in rats

Insecticide, termite control

Pentachlorophenol

Anti-estrogen, weak anti-androgen

No reduced fertility in mice and rats

Biocide, wood preservative, pre-harvest defoliant in cotton

Methoxychlor

Estrogen, anti-androgen

Testicular atrophy, decreased sperm production, testosterone levels in rats and mice. Reduced fertility in both genders. Thyroid inhibitor

Insecticide (fruits, vegetables, and grain storage bins, mushroom houses, dairies, livestock)

Hexachlorocyclohexane

Reduced fertility

Changes in the levels of sex hormones

insecticide (fruit and vegetable crops, including greenhouse vegetables, tobacco and forest crops), ointments to treat head and body lice, and scabies

α‎-HCH

Weak anti-androgen

β‎-HCH

No effect

Weak estrogen-like effects in mice and rats

(lindane) γ‎-HCH

Weak anti-androgen

No estrogen effect Impaired steroid synthesis in Leydig cells

Testicular atrophy, decreased sperm production, testosterone levels in rats and mink

δ‎-HCH

Weak anti-androgen

Mirex and photomirex

Weak estrogen. No anti-androgenic effect

Reduced fertility due to testicular degeneration

Affects thyroid and parathyroid

Termiticide

Nonachlor (cis- and trans-)

Anti-estrogen. Inhibits aER binding of [3H]17 β‎-estradiol

Sex-reversal in alligator embryos and turtles

Termite control

Toxaphene

Weak estrogen Inhibition of ACTH-stimulated corticosterone synthesis in the adrenal cortex

Thyroid inhibitor

Insecticide, biocide

Trans-nonachlor

Weak estrogen Anti-androgen

Insecticide

Carbamates and Thiocarbamates

Aldicarb

Weak estrogen

No reproductive effects

Nematicide

Benomyl (and its breakdown product carbendazim)

Microtubule disruptor Weak estrogen

Decreased sperm production in adult male rats

Fungicide (field crops, fruits, nuts, ornamentals, mushrooms, and turf)

Bendiocarb, methomyl, and oxamyl

Weak estrogens

No decrease of fertility in rats

Insecticides, acaricides, nematicides

Carbaryl

Anti-estrogen

Thyroid inhibition and reduced fertility in several animal species

Conflicting results on reduced fecundability

Insecticide

Carbofuran

Testicular damage in dogs

Broad spectrum insecticide

Chlorpropham

Anti-androgen

Herbicide, growth regulator

Mancozeb

Thyroid inhibitor in rats

Goitrogen

B

Fungicide

Maneb and Metiram

Thyroid inhibitors in several animal species

No reproductive effects

Fungicides

Methiocarb

Weak estrogen and anti-androgen

Insecticide

Molinate

Reduced fertility

No reproductive effects

Herbicide (rice crops)

Pirimicarb

Weak estrogen

Insecticide

Propamocarb

Weak estrogen

Fungicide

Propoxur

Weak estrogen

Reduced fertility and lactation in female rats

Insecticide

Thiram

Infertility in male mice, delayed estrous cycle in female mice

A

Fungicide, animal repellent

Zineb

Thyroid inhibitor in several animal species

Reduced fertility in rats

Fungicide

Ziram

Reduced fertility in female rats ans mice, and in male rats Testicular atrophy

Fungicide on almonds and stone fruit

Organophosphates

Azinphos-methyl

Anti-androgen

Insecticide, baaned in the EU

Chlorpyrifos

Weak estrogen.

No reproductive effects

A

Insecticide and acaricide for crops and livestock

Dichlorvos

Anti-androgen

Insecticide

Dimethoate

No reproductive effects

Reduced fecundability

D

Insecticide for 40 different crops, lawns, termiticide in buildings, pet collars

Fenitrothion

Anti-androgen

Insecticide

Fenthion

Anti-androgen

Insecticide, avicide, and acaricide

Glyphosate

Reproductive changes at very high doses

Reduced fecundability

D

Herbicide

Methamidophos

Reduced number of deliveries in female rats

Reduced sperm count and viability

Insecticide, acaricide and avicide

Methyl parathion and malathion

Inhibits catecholamine secretion

No reproductive effects in rats

D

Insecticide for various crops, livestock, parasite control

Parathion

Increased nocturnal synthesis of melatonin Gonadotrophic hormone inhibition

Insecticide for various crops

Pirimiphos-methyl

Anti-androgen

Insecticide

Tolclofos-methyl

Weak estrogen

Insecticide

Trichlorfon

Reduced fertility and increased embryonic deaths in rats

Insecticide for various crops, parasite control, livestock

Other Pesticides

Amitraz

Decreased fertility in rats

Insecticide (cotton and animals)

Amitrole

Thyroid inhibitor in several animal species

Herbicide

Atrazine

Weak estrogen, Weak anti-androgen Inhibits aER binding of [3H]17β‎-estradiol

Damage to adrenal glands

Impairment of steroid hormone metabolism

Herbicide (rice and other crops)

Abamectin

Reduced male fertility in several mammalian species Decrease in sperm count

B

Insecticide

Azadirachtin

Infertility in several animal species

Insecticide

Bromopropilate

Weak estrogen. Anti-androgen

Acaricide

Bupirimate

Thyroid effects in rats

C

Fungicide

Captan

Fetal loss or reduced weight at birth in mice

Reduced fecundability

D

Fungicide (apple production, ornamental and vegetable crops)

Chlomethoxyfen

Anti-androgen

Herbicide in rice crops.

Chlornitrofen

Anti-androgen

herbicide

Clofentezine

Thyroid disruptor

No reproductive effects

Acaricide

Cycloprothrin

Anti-estrogen

Pyethroid insecticide

Cyfluthrin

Weak estrogen and anti-androgen

Pyethroid insecticide

Cyhalothrin

Anti-estrogen, anti-androgen

Pyethroid insecticide

Cypermethrin

Weak estrogen

Pyethroid insecticide

Cyprodinil

Anti-androgen

Fungicide

2,4-D

No reduction in fertility

Increase in thyroid and ovarian weights.

Reduced fecundability

A

Herbicide (wheat, rice and and other crops, lawn, pasture, home, garden)

Deltamethrin

Weak estrogen

Pyethroid insecticide

Dibromochloropropane

Infertility in rabbits (atrophy of testes) testicular toxicant

Infertility

Potent Insecticide (banana plantations)

Dicamba

No reduction in fertility in rats and rabbits

Reduced fecundability

D

Herbicide (pastures, non crop areas, roadways to control weeds)

Dimethomorph

Anti-androgen

Fungicide (potatoes)

Dinoseb

Reproductive effects in rats

Herbicide in various field crops; insecticide in grapes

Ethylene dibromide

Reduced sperm count in bulls

Reduced sperm count and quality

Postharvest fumigant

Ethoxyquin

Anti-androgen

Antioxidant used as food preservative

Etofenprox

Anti-estrogen

Pyethroid insecticide

Fenbuconazole

Thyroid inhibitor Weak estrogen

Fungicide

Fenhexamid

Anti-androgen

Fungicide

Fenvalerate

Weak estrogen and anti-androgen

Pyethroid insecticide

Fipronil

Thyroid disruptor

Reproductive toxicant in rats

Insecticide

Fludioxonil

Anti-androgen

Fungicide

Hexachlorobenzene

Decreased male fertility

No estrogenic effects

Fungicide used to dress seed and treat soil Contaminant of PCNB

Imazalil

Anti-androgen

Fungicide

Ioxynil

Compete with T4 in binding plasma proteins

Increase in thyroid function

No reproductive effects

B

Herbicide

Iprodione

Binds the AR receptor; interference with thyroid hormones

Severe effects on prostate, adrenal glands in dogs and male reproductive organs in rats

C

Fungicide

Linuron

Androgen receptor agonist

Anti-androgenic

No reproductive effects

B

Herbicide (soybean, cotton, potato, corn, carrots, celery, sorghum, and asparagus)

Metolachlor

Weak estrogen

Testicular atrophy in rats

No reproductive effects in mice

Herbicide

Metribuzin

Estrogenic activity

Thyroid effects

No reproductive effects

C

Herbicide

Myclobutanil

Antiestrogenic

Effects on prostate, adrenal glands, and male reproductive organs in rats

C

Fungicide

Nonyl-phenol

Weak estrogen

Molluscicide

O-Phenyl phenol

Anti-androgen

Fungicide

Pentachloronitro

benzene (PCNB)

Thyroid inhibitor

Fungicide used to dress seed and treat soil

Permethrin

Weak estrogen Anti-androgen

Pyethroid insecticide

Prochloraz

AR antagonism, aromatase inhibition Weak estrogen

Effects on ovaries, prostate and thyroid

Fungicide

Procymidone

Anti-androgen

Anti-androgen in rats

Fungicide

Prodiamine

Thyroid disruptor

Herbicide

Propyzamide

Effects on thyroid and testes

Herbicide

Pyrazoxyfen

Anti-estrogen

Herbicide

Pyrimethanil

Anti-androgen

Thyroid inhibitor

No reproductive effects

Fungicide

Quinoxyfen

Anti-androgen

Fungicide

Simazine

No reproductive effects in rats Distrophy and necrosis of germ cells in sheep

Herbicide, submerged weeds and algae control in large aquariums, ponds and fish hatcheries

Spiromesifen

Thyroid disruption, female reproductive toxicity

C

Insecticide

Tebuconazole

Anti-estrogen and anti-androgen

C

Fungicide

Tetramethrin

Anti-estrogen

Insecticide

Thiacloprid

aromatase induction in rat liver

Thyroid and reproductive effects, cancer in reproductive organs

B

Insecticide

Thiazopyr

Thyroid disruptor

No reproductive effects

Herbicide

Thiophanate-methyl

Thyroid effects

C

Fungicide

Tribenuron-methyl

Weak estrogen

herbicide

Tributyltin

Short-term decrease in the activity of the pituitary-thyroid axis in rats

No long-term effects.

Antifouling agent on ships, boats, and mariculture pen nets

Pseudoermaphroditism in gastropods

Triflumizole

Anti-estrogen

Fungicide

Vinclozolin

Anti-androgen Weak estrogen

Demasculinizing effects in rats

No reproductive effects

Fungicide (grapes, vegetables, strawberries, fruit, ornamentals)

(*) Categorization of endocrine disrupters for regulatory purposes proposed by the UK-German Working Group for 98 selected pesticides for which human health endocrine disrupting assessments were conducted.

Sources: Cocco, Fadda, & Melis, 2006; DeCoster & van Larebeke, 2012; Ewence, Rumsby, & Johnson, 2013.

Based on the results of a competitive assay on proliferation of MCF-7 cells (an estrogen-dependent human breast cancer cell line), it has been estimated that the blood concentration of o,p’-DDE, the most potent xenoestrogen to significantly compete with estradiol in binding the estrogen receptor, would be not less than 30–180 μ‎g/ml in fertile women and 10–70 μ‎g/ml in postmenopausal women and men (Cocco, 2002).

Recently, a UK–German Working Group has proposed a categorization of endocrine disrupters for regulatory purposes for 98 selected pesticides for which human health endocrine-disrupting assessments were conducted, combining information from the ICPS classification scheme of pesticides with the available information on the endocrine effects in human, animal, and experimental studies (Bundesinstitut fur Risikobewertung, 2011). When endocrine-disrupting activities appear at or below the dose threshold with the application of a GHS-CLP category 1 or category 2 after repeated exposure either oral, dermal, or by inhalation, in short-term, medium-term, of chronic animal studies, the substance should be considered to pose a human health risk requiring consideration for regulatory action within the European Community (Ewence, Brescia, Johnson, & Rumsby, 2015). The UK–German Working Group assessments assigned each substance to one of four groups based on the mammalian toxicology or ecotoxicology data: Group A includes substances requiring additional information; Group B, endocrine disrupters more likely to pose a human health risk; Group C, endocrine disrupters less likely to pose a human health risk; and Group D, substances not considered to be an endocrine disrupter based on the mammalian toxicology data. The categorization resulting from such assessment is also reported in Table 5.

The ability of the so-called xenoestrogens to interfere with natural hormones by interacting with the same receptors depends on the dose and the receptor affinity with reference to the natural estrogen. The E-screen assay (based on the dose-related estrogen-dependent proliferation of MCF-7 cells, an estrogen-sensitive human breast cancer cell line) measures the relative potency of xenoestrogens (Soto et al., 1995). Outcomes of the E-screen assay are twofold: (a) the relative proliferative potency (RPP; the ratio between the estradiol concentration inducing maximal proliferation and the concentration of the test xenoestrogen required to achieve the same effect); and (b) the relative proliferative effect (RPE; 100 times the ratio between maximal cell yield achieved with the xenoestrogen and that obtained with estradiol). Table 6 shows that the estradiol concentration required to induce maximal cell yields ranges between 10 and 100 picomoles; on the other hand, xenoestrogens may achieve a comparable effect for concentrations one million times greater, in the range of micromoles.

Table 6. The Estrogenic Potential of Some Pesticides and Therapeutic Hormones (with Reference to Estradiol) Based on the In Culture “E. Screen” Assay

Compound

Concentration

RPE (%)

RPP (%)

17β‎-Estradiol

10pM

100.00

100.00

DDT (technical grade)

10μ‎M

79.61

0.0001

o,p’-DDT

10μ‎M

86.14

0.0001

p,p’-DDT

10μ‎M

71.00

0.0001

Dieldrin

10μ‎M

54.89

0.0001

Endosulfan (technical grade)

10μ‎M

81.25

0.0001

1-Hydroxychlordane

10μ‎M

40.00

0.0001

Kepone

10μ‎M

84.00

0.0001

Methoxychlor

10μ‎M

57.00

0.0001

Toxaphene

10μ‎M

51.90

0.0001

Source: Soto et al., 1995.

In the real world of pesticide manufacture and use, multiple pesticide exposures occur within a short time span, with different types of pseudo-endocrine effects which can interact among them in unpredictable ways either synergistically or antagonistically. Endocrine disruptors can act through nuclear receptors and through bound estrogen receptors; they can interact with cytoplasmic targets, modulate nitric oxide, and interfere with hormone metabolism; and they can cause changes in DNA methylation or histone modifications or genomic instability. Therefore, it is quite difficult to predict a threshold concentration for the endocrine-disrupting effects of one pesticide only based exclusively on the relative potency of this single pesticide once linked to the estrogen receptor. Nevertheless, based upon the possible range of circulating estradiol levels, men, postmenopausal women, and children are expected to be more sensitive to xenoestrogens (Cocco, 2002).

Cancer

In 1991, IARC classified “occupational exposures in spraying and application of non-arsenical insecticides” as a group as “probable human carcinogens” (Group 2A) (IARC, 1991). This group is composed of 61 pesticides (including 26 insecticides, 12 fungicides, 17 herbicides, and 6 fumigants) examined in 8 different IARC monographs, among the 985 agents and groups of agents examined in 43 years of IARC Monographs. Some of these pesticides have been banned or abandoned for some decades, although a few of these keep being used in developing countries (Table 7). Arsenic and arsenical pesticides, 1,2-dichloropropane and lindane, are Group 1 human carcinogens. Group 2A, probable human carcinogens, includes the fungicide captafol (restricted in the United States and most countries since 1999), the herbicide glyphosate, and the insecticides malathion, diazinon, DDT (still allowed only for public health purposes), and ethylene dibromide (used as a grain fumigant). As for the rest, the inadequate or not available evidence from human studies is coupled with the limited or inadequate evidence from experimental animal studies.

Table 7. Evidence of Carcinogenicity and Summary Evaluation of Human Carcinogenicity of Pesticide Compounds examined in the IARC Monographs N. 1-114 (S= sufficient; I = inadequate; ND = no data available as of February 2016).

Compounds

Year

Man

Animal

Summary evaluation of human carcinogenicity

Insecticides

Aldicarb

1991

ND

I

3

Aldrin

1987

ND

I

3

Aramite

1987

ND

S

2B

Arsenic and arsenical compounds

1987

S

L

1

Carbaryl

1987

ND

I

3

Chlordhane/eptachlor

2001

I

S

2B

Chlordecone

1987

ND

S

2B

Chlorobenzilate

1987

ND

L

3

DDT

2015

L

S

2A

Deltamethrin

1991

ND

I

3

Diazinon

2015

L

L

2A

Dichlorvos

1991

I

S

2B

Dicofol

1987

ND

L

3

Endrin

1987

ND

I

3

Fenvalerate

1991

ND

I

3

γ‎-Hexaxchlorocyclohexane (lindane)

2015

S

S

1

Malathion

2015

L

S

2A

Methoxychlor

1987

ND

I

3

Methyl-parathion

1987

ND

I

3

Mirex

1987

ND

S

2B

Parathion

2015

I

S

2B

Permethrin

1991

ND

I

3

Terpene polychlorinates (Strobane)

1987

ND

I

3

Tetrachlorvinphos

2015

I

S

2B

Toxaphene

2001

ND

S

2B

Trichlorfon

1987

ND

I

3

Fungicides

Captafol

1991

ND

S

2A

Captan

1987

ND

L

3

Chlorothalonil

1999

ND

L

2B

Ferbam

1987

ND

I

3

Hexachlorobenzene

2001

I

S

2B

Hexachlorophene

1987

ND

I

3

Maneb

1987

ND

L

3

Pentachlorophenol and polychlorophenols as a class

1999

L

S

2B

Quintozene

1987

ND

I

3

Insecticides

Sodium ortho-phenylphenate

1999

ND

S

2B

Thiram

1991

I

I

3

Ziram

1991

ND

L

3

Herbicides

Amitrole

1987

I

S

2B

2,4-D

2015

I

L

2B

Atrazine

1999

I

S

3

Chlordimeform

1987

ND

I

3

Chloropropham

1987

ND

I

3

Diallate

1987

ND

L

3

Fluometuron

1987

ND

I

3

Glyphosate

2015

L

S

2A

MCPA

1987

I

L

2B

Monuron

1991

ND

L

3

Nitrofen

1987

ND

S

2B

Picloram

1991

ND

L

3

Propham

1987

ND

I

3

Simazine

1999

I

L

3

Sulfallate

1987

ND

S

2B

2,4,5-Trichlorophenoxyacetic acid

1987

I

I

2B

Trifluralin

1991

I

L

3

Fumigants

1,2-Dibromo-3-chloropropane

1987

I

S

2B

1,3-Dichloropropene

1999

ND

S

2B

1,2-Dichloropropane

2014

S

L

1

Ethylene dibromide

1987

I

S

2A

Methyl bromide

1999

I

L

3

Piperonyl butoxide

1987

ND

I

3

(S= sufficient; I = inadequate; ND = no data available as of February 2016).

Thousands of chemicals are now available to farmers to treat plant diseases and protect their crops; their use changes year by year, across countries and within each country, by type of crop and by type of phytopathology. Therefore, the difficulty of conducting epidemiological studies of the long-term effects of agrochemicals is reflected in the inadequate information on their human carcinogenicity and the absence of evaluation by international scientific and regulatory agencies (Cocco et al., 2013).

The U.S. Agricultural Health Study is an extensive prospective longitudinal study of cancer and other health outcomes in a cohort of licensed pesticide applicators (including farmers) and their spouses in the states of Iowa and North Carolina to assess health risks associated with exposure to specific agricultural chemicals, with the support of a detailed retrospective exposure assessment and with proper consideration of lifestyle and genetic factors (Alavanja et al., 1996). The study was started in 1993 as a collaborative effort involving investigators from National Cancer Institute, the National Institute of Environmental Health Sciences, the Environmental Protection Agency, and the National Institute for Occupational Safety and Health. The study began by collecting baseline information from participants at enrollment (1993–1997). Overall, 20,235 pesticide applicators and 1683 spouses were recruited. In two subsequent phases, 1999–2003 and 2005–2010, follow-up telephone interviews were conducted in 64% of private applicators, 59% of commercial applicators, and 74% of spouses. Questionnaire information included farming practices, lifestyle, and health and diet; a DNA sample from a buccal swab was also acquired. The interview was repeated in 2005–2010 by 46% of private applicators and 62% of spouses who participated in the baseline phase. An additional follow-up was initiated in 2013 with a questionnaire by mail, telephone, or through the Internet, this time including also those who had not participated in the previous phases. Thus far, the Agricultural Health Study has greatly contributed to the identification of cancer risks in relation to exposure to individual chemicals not previously evaluated. Table 8 lists the cancer outcomes associated with exposure to pesticides, including the compounds classified by IARC for which epidemiological studies were conducted, and those not yet examined for which suggestions emerged from the Agricultural Health Study or other studies. Only active compounds are listed in Table 8; contaminants (e.g., tetrachlorodibenzodioxin [TCDD], a group 1 human carcinogen according to IARC, which contaminated Agent Orange and other phenoxy herbicide preparations and caused environmental contaminations following industrial accidents) are not included.

Table 8. Individual Pesticide Compounds for Which Associations with Cancer Risk Have Emerged from The Agricultural Health Study and Other Studies.

Pesticide

IARC classification

Cancer site

Epidemiological evidence

Ref.

Alachlor

Not evaluated

Leukemia

Positive association in the highest exposure category

Alavanja, Ross, & Bonner, 2013

Aldicarb

3

Colorectum

Significant upward trend with exposure level (small numbers)

Christensen et al., 2010

Aldrin

3

Prostate

Increased risk in subjects with positive family history of PC.

Alavanja, Ross, & Bonner, 2013

Atrazine

3

NHL, thyroid

Positive associations with NHL in subjects with t(14:18). Suggestive increase in thyoid cancer (small numbers)

Alavanja, Ross, & Bonner, 2013; Guyton et al., 2015

Butylate

Not evaluated

Prostate, NHL

High risk in long duration exposed; interaction with family history (nonsignificant)

Freeman et al., 2011

Captan

3

Multiple myeloma

Positive association with MM risk

Alavanja, Ross, & Bonner, 2013

Carbaryl

3

Multiple myeloma, skin melanoma

Positive association with MM, and melanoma (long duration)

Alavanja, Ros,s & Bonner, 2013; Koutros et al., 2015

Chlordane

2B

Leukemia, NHL (inconsistent)

Positive association with leukemia risk; inconsistent results on risk of NHL

Alavanja, Ross, & Bonner, 2013

Chlordecone

2B

Prostate

Positive association in the highest exposure category

Alavanja, Ross, & Bonner, 2013

Chlorpyrifos

Not evaluated

Colorectum, lung

Significant upward trend with exposure

Christensen et al., 2010; Kang et al., 2008

Coumaphos

Not evaluated

Prostate

Increased risk in subjects with positive family history of PC.

Barry et al., 2012

2,4-D

2B

NHL

Inadequate evidence for inconsistent findings.

Loomis et al., 2015

DDT

2A

Liver, NHL, testis

Limited evidence for Inconsistent findings with serum DDE levels. Inadequate evidence for prostate and breast

Loomis et al., 2015

Diazinon

2A

NHL, leukemia and lung cancer

Increasing trends in risk after adjustment for other pesticides and confounders. Limited evidence.

Guyton et al., 2015

Dicamba

Not evaluated

Lung, colon

Significant upward trends

Samanic et al., 2006

Dieldrin

3

NHL, prostate cancer

Inadequate evidence for inconsistent findings for NHL. Suggestions for prostate cancer.

Alavanja, Ross, & Bonner, 2013

S-Ethyl dipropyl carbamothioate (EPTC)

Not evaluated

Leukemia, colon and pancreatic cancer

Relatively small number of exposed in the high exposure category, only. Significant trend for pancreatic cancer

Alavanja, Ross, & Bonner, 2013; Andreotti et al., 2009

Fonofos

Not evaluated

Prostate cancer, leukemia.

Trend in risk of prostate cancer. Positive association with leukemia; interaction with genetic variants in 8q24, base excision repair, nucleotide excision repair.

Alavanja, Ross, & Bonner, 2013

Glyphosate

2A

NHL

Limited evidence of a positive association with NHL risk

Guyton et al., 2015

Hexachloro benzene

2B

NHL, prostate

Positive associations with plasma level of HCH. Inadequate evidence. Inconsistent association with prostate cancer

Alavanja, Ross, & Bonner, 2013

Imazaquin

Not evaluated

Bladder

Positive association

Koutros et al., 2015

Imazethapyr

Not evaluated

Bladder, colon

Association observed only among nonsmokers

Koutros et al., 2015

Lindane

1

NHL

Consistent association for NHL

Loomis et al., 2015

Malathion

2A

NHL, prostate

Limited evidence for NHL and prostate cancer. Genotoxicity, oxidative stress, Inflammation, receptor-mediated effects, and cell proliferation or death

Guyton et al., 2015

Maneb/mancozeb

3

Skin melanoma

Association with high duration exposure

Dennis, Lynch, Sandler & Alavanja, 2010

Metolachlor

Not evaluated

Liver, follicular lymphoma, lung

Significant upward trends with exposure

Alavanja et al., 2004; Silver et al., 2015

Methyl bromide

3

Prostate, stomach

Nonsignificant association among subject with positive family history of PC. Significant trend for stomach cancer.

Alavanja, Ross, & Bonner, 2013; Barry et al., 2012

Methyl-chloro phenoxyacetic acid (MCPA)

2B

NHL

Positive association among subjects with asthma or hay fever.

Alavanja, Ross, & Bonner, 2013

Metribuzin

Not evaluated

Leukemia, NHL

Significant upward trend for lymphohemopoietic malignancies, nonsignificant for leukemia and NHL

Alavanja, Ross, & Bonner, 2013

Mirex

3

NHL

Inconsistent epidemiological results

Alavanja, Ross, & Bonner, 2013

Parathion

2B

Skin melanoma

Association with high duration exposure

Dennis et al., 2010

Pendimethalin

Not evaluated

Pancreas, lung

Significant trend with exposure level

Alavanja et al, 2004; Andreotti et al., 2009

Permethrin

3

Multiple myeloma

Significant interaction with genetic variants in 8q24

Alavanja, Ross & Bonner, 2013

Phorate

Not evaluated

Prostate

Increased risk in subjects with positive family history of PC.

Mahajan, Bonner, Hoppin, & Alavanja, 2006

Simazine

3

Prostate

Inconsistent epidemiological results

Alavanja, Ross, & Bonner, 2013

Terbufos

Not evaluated

Prostate, lung, leukemia, NHL

Nonsignificant trends in risk. Significant interaction with genetic variants in 8q24

Alavanja, Ross, & Bonner, 2013; Bonner et al, 2010

Toxaphene

2B

NHL

Positive association with cases with t(14:18)

Alavanja, Ross, & Bonner, 2013

Trifluralin

3

Colon, kidney

Elevated risk for colon cancer in the highest exposure category. Nonsignificant association with kidney cancer

Kang et al., 2008

Other Health Effects

Central Nervous System and Peripheral Nervous System Effects

Acute high-level exposure to organophosphates, carbamate, and organochlorine pesticides is a well-established cause of neurotoxic effects, while the association of these effects with chronic exposure to low-moderate levels is more controversial (Kamel & Hoppin, 2004). The neurotoxicity of organophosphates is related to the inhibition of acetylcholinesterase and the resulting hyperstimulation of postsynaptic receptors. In less severe cases, symptoms (e.g., headache, dizziness, nausea, vomiting, pupillary constriction, and excessive sweating, tearing, and salivation) occur within minutes. More severe intoxications present with muscular weakness, bronchospasm, and twitching, with possible progression to convulsions and coma (Kamel & Hoppin, 2004). A delayed neuropathy due to axonal death can follow as a result of the acute organophosphate inhibition of an esterase and can be irreversible (Keifer & Mahurin, 1997). The long-term consequences of organophosphate poisoning include cognitive and psychomotor deficits, decreased vibration sensitivity, and motor dysfunction, observed as long as 10 years after an acute episode even with mild intoxications by carbamates or organophosphates not requiring hospitalization (Kamel & Hoppin, 2004; Wesseling et al., 2002). Results from studies of mild acute intoxication by organophosphates vary by country, with positive findings mainly in developing countries where exposure was presumably higher.

Chronic low-level exposure to organophosphates is also accompanied by a higher frequency of self-reported symptoms, such as headache, dizziness, fatigue, insomnia, nausea, chest tightness, and breathing difficulty; impaired neurobehavioral performance, such as confusion, memory loss, and difficulty in concentrating, confirmed by batteries of neurobehavioral tests; mood disorders; and sensory and motor dysfunction, such as weakness, tremors, numbness, tingling, and visual and hearing disturbances (Crawford et al., 2008; Kamel & Hoppin, 2004; Starks et al., 2012a). Such effects are not necessarily related to acetylcholinesterase inhibition (Pope, 1999). The same symptoms have been described in association with exposure to DDT and fumigants, although negative findings have also been reported. Direct measurement of motor or sensory nerve function (e.g., vibration sensitivity, smell, sense of balance from damage to the vestibular function, or visual contrast sensitivity) resulted in inconsistent findings in relation to exposure to organophosphates, DDT, or fumigants (Kamel & Hoppin, 2004). In the Agricultural Health Study, abnormal toe proprioception was associated with six organophosphates, while null associations were observed with electrophysiological tests, hand strength, sway speed, and vibro-tactile thresholds (Starks et al., 2012c).

An extensive body of literature suggests an increased incidence of Parkinson’s disease among pesticide-exposed workers. However, inconsistent findings have also been published, and most studies were unable to identify specific pesticides. Paraquat is known to induce selective damage of the dopaminergic neurons involved in Parkinson’s disease, and experimental animal models and several case reports have described Parkinson’s disease cases in exposed workers. However, exposure to organochlorines, organophospates, carbamates, and dithiocarbamates has also been associated with the risk of Parkinson’s, as has exposure to the herbicide glyphosate and the fungicides diquat and maneb (Kamel & Hoppin, 2004).

A meta-analysis was suggestive for an association of amyotrophic lateral sclerosis (ALS) with pesticide exposure in general; nonsignificantly increased risks were found in association with organochlorine insecticides, pyrethroids, herbicides, and fumigants, and specific compounds such as aldrin, dieldrin, DDT, and toxaphene (Kamel et al., 2012).

The risk of Alzheimer’s disease was also associated with exposure to pesticides in general in two case-control studies. However, no specific compounds have been identified. Such results are also difficult to interpret, as Alzheimer’s disease is characterized by the loss of cholinergic neurons, which is why cholinesterase inhibitors are used in its treatment (Kamel & Hoppin, 2004). Interestingly, in a neurobehavioral study of participants in the Agricultural Health Study, exposure to chlorpyrifos, coumaphos, parathion, phorate, and tetrachlorvinphos were associated with improvements in verbal learning and memory; coumaphos was associated with better motor speed and visual scanning performance; and parathion with better sustained attention (Starks et al., 2012b).

Liver, Kidney, and Skin Disorders

Acute paraquat poisoning by ingestion is relatively frequently followed by toxic hepatitis after about one week, and about three quarters of patients subsequently develop kidney failure, but no fatalities have been reported (Yang et al., 2012). Half of the patients of intentional or accidental endosulfan poisoning also developed acute toxic hepatitis, along with other complications (such as rhabdomyolisis and refractory epilepsy) (Moon & Chun, 2009); mortality among these latter subjects was around 30%. At high doses, 2,4-D poisoning also damages the liver and kidney and irritates mucous membranes (Garabrant & Philbert, 2002).

Under the conditions of regular occupational exposure, indoor residual spraying with DDT lasting six months was not followed by changes in the serum level of liver enzymes (Bimenya et al., 2010). Among Brazilian residents in an area heavily contaminated with the organochlorine beta-hexachlorocyclohexane (β‎-HCH), p,p’-DDE, and hexachlorobenzene (HCB), serum bilirubin levels were the only parameter significantly associated with β‎-HCH blood level but not with the blood levels of the other organochlorine pesticides (Freire, Koifman, & Koifman, 2015).

The chlorophenoxy herbicides may cause dermatitis following prolonged skin contact, and prolonged high-level exposure to TCDD causes chloracne (i.e. inclusion cysts, comedones, and pustules) in the face and other parts of the body (Legaspi & Zenz, 1994). Also, numerous compounds have been described as responsible for contact or allergic forms of dermatitis, frequently due to the presence of solvents as co-formulants (Colosio & Rubino, 2015).

Prevention

In the industrialized world, the concern following industrial and community pesticide poisoning events has generated more careful monitoring systems of pesticide production and use, as well as regular monitoring programs of their residual concentration in foodstuffs along the chain of market distribution. Several compounds are simply not allowed at any concentration; therefore, products imported from other geographic areas must be certified as exempt from residuals of these prohibited compounds, and their detection leads to the withdrawal of the contaminated products (Colosio & Rubino, 2015). For authorized products, an acceptable daily intake (ADI) and a safety level expressed as acute reference dose (ARD) have been established based on toxicological tests in experimental animals. ADI values concern the regular condition of commercialized foodstuffs, and they are published by the U.S. Department of Agriculture and by DG Sanco in Europe.

In pesticide manufacturing and packaging, basic industrial hygiene principles apply, involving the recognition, constant evaluation, and control of potential health hazards, taking into account all possible routes of exposure. Dermal absorption can be more relevant than inhalation, and therefore proper clothing and gloves need to be worn and cleaned at the facility. Routine washing of hands, face, and neck and a shower at the end of the work shift are advised. To prevent oral consumption, smoking, eating or storing food, cigarettes, or cosmetics in areas with potential pesticide contamination should not be allowed. To prevent inhalation, the use of properly filtered masks while handling pesticides should be enforced, and air-supplied respirator helmets should be provided when necessary to protect against particularly toxic chemicals. Also, routine periodic decontamination should be scheduled for both the work areas and the communal work areas (e.g., such as cafeterias, locker rooms, toilets, offices, and laboratories). Finally, access to potentially contaminated areas in the plant should be limited to trained employees only.

When applying pesticides in a farm, or whatever other use, a written registry should be kept indicating the date, the product used, its amount, crop, and purpose, as well as the names of the applicators and a checklist of the necessary protective equipment.

Preplacement medical examinations are provided to all workers to identify pre-existing illnesses or conditions that might limit fitness to work and to provide a baseline for any subsequent adverse health outcomes. With regard to periodic testing, when organophosphate or carbamate use is expected to occur, the acetyl cholinesterase activity in the serum and the red blood cells should be measured at baseline and periodically reassessed, as well as any other suitable biological monitoring. Such surveillance programs need to be accompanied by an appropriate educational program on the work procedures necessary to minimize exposure, as well as highlighting the importance of wearing personal protective equipment even in unfavorable weather conditions; there should also be discussion of the potential acute and long-term health effects, including infertility and cancer, to be expected if these precautionary measures are not effectively implemented (Legaspi & Zenz, 1994). These educational messages should be updated and re-introduced to the workers at regular intervals.

Implementing preventive action in developing countries is quite another story. In developing countries, farmers rely on information directly from the chemical companies, regulatory controls are frequently inadequate, and educational programs on the hazards posed by misuse of pesticides are seldom implemented. Wearing protective gear in subequatorial countries is less tolerable because of high temperature and humidity; along with lack of proper education, poverty and the natural environment might contribute to what observed in some surveys in these countries: pesticide applicators seldom use personal protective equipment, and women often participate with their babies attached to their backs (Naidoo et al., 2010; Oesterlund et al., 2014). Consensus exists among international organizations, including the Food and Agriculture Organization of the United Nations (FAO), the World Health Organization, and the World Bank, that hazardous pesticides should not be accessible to farmers unless they are educated about their proper management and storage and the use of protective gear. Therefore, FAO recommends withdrawal of hazardous pesticides from the market in developing countries (FAO, 2013).

A total ban on the use of pesticides is unlikely to happen in the foreseeable future. However, the shift of primary production and the manufacturing industries from developed toward developing countries in the globalized world has generated a differential pattern of exposure circumstances, with a phasing out of persistent organochlorine pesticides and more toxic pesticides in Europe (where stricter regulations are applied) and less restrictive attitudes toward occupational and environmental exposures in the developing world. Organic farming is growing in some parts of the United States and Europe, but it seems unlikely that it will become productive enough to comply with the increasing demand for good quality and safe agricultural products. Specific guidelines to limit the human health and environmental effects of improper handling and disposal of pesticides have been issued, and they are outlined in Table 9.

Table 9. Exposure Control Actions in the Workplace and the General Environment

Subject

Route of exposure

Preventive or corrective action

Applicator

Inhalation

  1. 1. Mix or load pesticides outdoors, in a well-ventilated area.

  2. 2. Wear appropriate respiratory protective equipment according to pesticide label instructions.

Ingestion

  1. 1. Do not eat, drink, or smoke during pesticide handling or application.

Dermal

  1. 1. Use personal protective equipment including chemically resistant gloves.

  2. 2. Remove all labor clothes after work; if pesticide-soiled, remove them as soon as possible.

  3. 3. Have a shower immediately after application.

Bystanders and children guardians

Inhalation

  1. 1. Do not stockpile pesticides. Purchase only what is needed for immediate application.

  2. 2. Dispose of pesticides properly, according to the label directions.

  3. 3. Report any symptoms possibly related to pesticide exposure to your doctor. Remind of the name of the product, the ingredients, and the first aid instructions on the product label.

  4. 4. When someone is applying pesticides outdoors near your home, stay indoors with your children and pets, and keep windows and doors closed.

Ingestion

  1. 1. Never store pesticides in cabinets with or near food.

  2. 2. Always store pesticides in their original containers, complete with labels that list ingredients, directions for use, and first aid in case of accidental exposure.

  3. 3. Never transfer pesticides to soft drink bottles or other containers.

  4. 4. Rinse fruits and vegetables with water and, if possible, peel them before eating.

Dermal

  1. 1. Do not enter and do not allow children to enter fields, lawns, or confined spaces after pesticides have been applied for the period specified on label instructions.

  2. 2. Encourage family members to remove shoes and labor clothes outside the home or as soon as possible after entering the home.

  3. 3. Vacuum rug and/or clean floors if soiled with pesticides.

  4. 4. Do not store pesticides in living areas or anywhere within the reach of children. Keep all pesticides in a locked cabinet in a well-ventilated utility area or garden shed.

  5. 5. Encourage family members exposed to pesticides to shower as soon as possible after exposure.

  6. 6. When soiled with pesticides, do not allow pets to enter the living areas of the home until cleaned.

  7. 7. Wash clothing soiled with pesticides separately from other laundry.

Regulatory agencies, scientific community and chemical manufacturers

All

  1. 1. Identify human carcinogens and remove them from the marketplace or greatly limit their use.

  2. 2. Identity the persistence and accumulation potential of pesticides and reduce the use of long-lived pesticides wherever possible.

  3. 3. Identify good pesticide work practices and educate the public in these practices.

  4. 4. Train properly certified professional applicators to handle pesticides in the fields and in major household disinfestations.

  5. 5. Design more effective pesticide containers and application equipment that minimizes pesticide exposure to the applicator and contact to children.

Source: Alavanja, Ross, & Bonner, 2013.

As mentioned in the introduction, research on the health effects of pesticides is particularly complicated because of the complex pattern of applications to different crops and their frequent changes over time to prevent pest resistance. Apart from professional pest control operators, exposures are usually intermittent and poorly documented. Besides, using exposure biomarkers to characterize exposure to the most popular pesticides is difficult, as they tend to have short half-life metabolites, and these might be not specific enough. Therefore, efforts must be made to extend educational programs to the agricultural workers in developing countries, starting from the proper registration of treatments applied, and including a checklist of the precautionary measures to be taken, date, type, and amount of the pesticide to be applied, and pest to be treated. Apart from the educational effectiveness of these procedures in raising concern about the potential health effects of pesticide use, the data gathered would be of utmost importance in replicating findings and confirming associations suggested from small-scale and poorly documented studies. Questions that remain to be solved include the specific long-term effects, including cancer and the neurodegenerative diseases, and the endocrine-disrupting and trans-generational effects associated with specific farm practices and specific pesticides. Education of pesticide applicators and proper data collection for future, better documented studies would be most effective in preventing acute effects and known long-term effects.

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