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Endocrine disrupting pesticides
Many pesticides are now suspected of being endocrine disruptors - chemicals that can lead to an increase in birth defects, sexual abnormalities and reproductive failure. Gwynne Lyons of WWF-UK examines the current evidence and potential for adverse effects to occur in both wildlife and human populations. Endocrine disrupting chemicals (EDCs) are substances that can cause adverse effects by interfering in some way with the body's hormones or chemical messengers. These substances are therefore called hormone disruptors or endocrine disruptors, as it is the endocrine glands that secrete the hormones. Hormones play a crucial role in guiding normal cell differentiation in early life forms, and so exposure to endocrine disrupting substances in the egg or in the womb can alter the normal process of development. Mature animals can also be affected, but it is the developing organism that is especially vulnerable. Exposure at this sensitive time may cause effects that are not evident until later in life, such as effects on learning ability, behaviour, reproduction and increased susceptibility to cancer and other diseases. Few official lists of suspected endocrine disruptors have been published. Table 1 details the pesticides that have been identified as potential endocrine disruptors in the list produced under the auspices of the Oslo and Paris Commissions (OSPAR). Table 2 details additional pesticides which might be endocrine disruptors and which feature on the World Wide Fund for Nature (WWF) list of chemicals in the environment reported to have reproductive and/or endocrine disrupting effects. However, for some of these substances, without further detailed investigation of their mode of action, it is not known whether their reproductive effects are actually the consequence of endocrine disruption. Apart from the pesticides documented in these two tables, others suspected of having endocrine effects include: metam natrium, methylbromide, carbendazim, prochloraz, dibromoethane (EDB), propanil, iprodione, thiram, diuron, diazinon and fenthion. These pesticides were amongst the 116 substances on which information was examined by EU experts, brought together by the European Commission in September 1999 for the prpose of drawing up a list of endocrine disrupting substances. Effects of EDCs
The effects that can be seen in an organism exposed to an endocrine disrupting chemical
(EDC) depend on which hormone system is targeted. For example, if an organism is
exposed to sex hormone disrupting pesticides in the womb, then the sort of effects that may
be evident include effects on sexual behaviour, structural deformities of the reproductive
tract, including intersex type conditions and undescended testes, deficits in sperm counts,
and effects on sex ratios. However, if the primary action is on the thyroid hormones, then as
these hormones are responsible for metabolism and normal brain development, exposure in
the womb may cause effects on intelligence and growth. Laboratory tests have confirmed
that endocrine disrupting chemicals do indeed cause such effects in exposed animals, but all
the effects listed above have also been noted in wildlife or humans heavily exposed to
endocrine disrupting pesticides or industrial chemicals.
Some endocrine disruptors may exert their action by interfering with the brain's release of
hormones, which in turn regulate the production of other hormones that control the growth
and the activity of many other endocrine glands. Indeed, the pituitary has been termed the
conductor of the endocrine orchestra, and pollutants that cause the pituitary region in the
brain to malfunction may therefore have multiple effects.
Pesticides that are POPs
There is particular concern about endocrine disrupting pesticides that are lipophilic (fat
loving), resistant to metabolism, and able to bioconcentrate up the food chain. This is
because these substances become stored in body fats and can be transferred to the
developing offspring via the placenta or via the egg. Predator animals (and humans) feeding
at the top of the food chain are at increased risk, particularly mammals because during breast feeding contaminants are again mobilised and transferred to the new born infant. Marine mammals may be most vulnerable, because not only do they carry large amounts of body fat, but also the oceans are the final sink for many persistent pollutants. Some persistent pollutants, including several pesticides, are carried in air and in water over several hundred miles, and so even wildlife and people living far away from where these substances are used are under significant threat. Some areas are especially vulnerable because these substances are redistributed to the colder northern regions in a process termed 'global redistillation' or the grasshopper effect. This transboundary nature of pollution has led to the negotiation of a global agreement to control persistent organic pollutants (POPs), which is due to be finalised in 2001. The United Nations Environment Programme Convention on POPs will initially focus on 12 substances, including the following pesticides: aldrin, chlordane, DDT, dieldrin, endrin, heptachlor, HCB, mirex, and toxaphene. Public interest coalitions such as the International POPs Elimination Network (IPEN), the Pesticides Action Network and WWF are pushing for the production and use of these POPs to be eliminated as soon as possible. DDT is, however, still used in several tropical countries. The challenge is for the global community to find other substances and regimes that are equally as efficacious in controlling malaria, and in this, WWF is certainly playing an active part. Unfortunately, even where it is now banned, exposure to DDT can still arise from a number of sources including: mobilisation of existing body burdens; from continued illegal usage; from sites contaminated in the past; and from continued usage elsewhere. Mechanisms of action
General
Endocrine disruptors can exert their effects in many ways. They can either bind to the
hormone's receptor and mimic the hormone, or block the action of the hormone.
Alternatively, they can stimulate or inhibit the enzymes responsible for the synthesis or
clearance of a hormone, and thereby give rise to an increased or decreased action of the
hormone.
In general, with regard to endocrine disruptors, concern is mostly focused on those
substances that cause endocrine mediated adverse effects at exposure levels lower than
those which cause other adverse effects.
Sex hormone disruptors The main hormone which gives rise to female characteristics is oestrogen, and the hormone mainly responsible for predominantly masculine characteristics is androgen. However, both sexes have both these hormones, although the levels of oestrogen are higher in females and androgens are higher in males. Many pesticides have now been found to have oestrogenic or anti-androgenic activity, and some bind to the androgen or oestrogen receptors. Those which have been found to bind to the oestrogen receptor include: ortho-phenylphenol, DDT and metabolites (although the anti-androgenic properties of p'p'DDE may be of greater importance); methoxychlor; chlordecone; dieldrin, endosulfan; 1-hydroxychlordene (a metabolite of chlordane); and toxaphene. Some of these can induce oestrogenic effects at relatively low levels. For example, administration of methoxychlor to the new born rat at a dose level of 0.5 µg per day caused accelerated puberty and accelerated loss of fertility. Similarly, new born female rats injected with 1 mg per day of o'p-DDT on days 2-4 after birth had early onset of puberty and accelerated loss of fertility. Even doses as low as 1µg/day of either of these substances, given to pregnant female mice on days 11-17 of pregnancy, causes effects on the territorial behaviour of male offspring. However, DDE induced eggshell thinning, one of the most well known effects noted in wildlife, is now not thought to result from DDE binding to a sex hormone receptor. Anti-androgenic pesticides that bind to the androgen receptor include: the dicarboximide fungicides, vinclozolin and procymidone; p'p'DDE; certain pyrethroids; and the herbicide linuron. Researchers have evaluated the potency of the following pyrethroids in terms of their interaction with androgen binding sites, and in descending order this was: fenvalerate > phenothrin > fluvalinate > permethrin > resmethrin. In the case of vinclozolin, it is the metabolites that are active anti-androgens. The dose levels at which effects are noted are fairly low. For example, at a vinclozolin dose level of 3 mg/kg/day, male rats exposed in the womb were feminised, in that abnormal numbers of nipples were seen. Similarly, at a dose level of 25 mg/ kg /day given from the fourteenth day of pregnancy to three days after birth, procymidone caused intersex characteristics in male rats, but these workers did not determine a no-observed adverse effect level. Linuron has a similar structure as the pharmaceutical anti-androgen, flutamide, and at a dose level of 40 mg/kg/day from weaning through puberty, it reduced seminal vesicle weights in male rats and delayed puberty. Pesticides which affect steroid synthesis and metabolism Numerous pesticides have been reported to affect hormone synthesis and/or metabolism. These include: the imidazole pesticides (such as propiconazole, epoziconazole and ketoconazole); fenarimol; TBT; and several organochlorine pesticides. Ketoconazole, for example, has been found to block steroid synthesis, and in pregnant rats exposed to 25mg/kg/day from the fourteenth day of pregnancy, giving birth was delayed and a reduced number of pups survived. The authors suggested that ketoconazole inhibited the synthesis of oestradiol near term, possibly by inhibiting aromatase activity. Another pesticide, fenarimol, is known to inhibit aromatase activity, and this has also been shown to delay birth. TBT is also believed to act by inhibiting aromatase, as it appears to act by blocking the conversion of testosterone to oestradiol. It therefore has well-known androgenic activity in molluscs, and for example, it can cause female dog whelk to grow penises (imposex) at concentrations as low as 2.5 nanogram per litre. Thyroid hormone disruptors Other pesticides can act on the thyroid. For example, the following substances can affect thyroid hormone levels: amitrole; ioxynil; and the dithiocarbamates (such as maneb, mancozeb, and zineb). Amitrole (or aminotriazole) appears to interfere with thyroid hormone synthesis and can cause cancer of the thyroid. It is a triazine herbicide, with a no observed adverse effect level for thyroid hyperplasia of 2mg/kg in the diet of rats. Similarly, alachlor, an aniline-type herbicide, is associated with thyroid follicular tumours in rats, and is believed to be an endocrine disruptor. Effects on brain With regard to pesticides that act on the brain, both organophosphate and the insecticidal carbamate pesticides can reduce acetycholinesterase (enzyme) activity, and hence block nerve impulses. This effect may be linked to the suppression of the brain's release of hormones that stimulate the gonads (the gonadotrophic hormones, which are follicle stimulating hormone (FSH) and leutinizing hormone (LH)). Some organophosphates have been associated with decreased egg production and reduced serum luteinizing hormone (LH) in birds, and similarly, carbamates have been associated with a reduced number of eggs. Also, in the males of several animal species, certain organophosphates and carbamates have been linked with effects on sperm. Some organophosphate pesticides have been suggested to cause abnormal menses, amenorrhea, and early menopause, and again these effects have been linked with a perturbation of LH release from the pituitary. Likewise, exposure to carbaryl has been associated with adverse effects on human semen. Aldicarb, an extremely toxic systemic carbamate insecticide, is also suspected of being an endocrine disruptor. When given to female pregnant rats at low levels of 1-100mg/kg, it has been shown to depress acetylcholinesterase activity more in the foetus than in the mother. It has also been suggested that there may be a link between low level exposure and effects on the immune system. Assessing mode of action The processes involved are much more complicated than this summary might suggest, and for example, not only are there are many feedback mechanisms, but also the nervous, endocrine and immune systems are interconnected. Our knowledge of hormonal actions and receptor sites is also far from complete, and two receptors for oestrogen have recently been identified. In addition, apart from the sex hormones and thyroid hormones there are many other hormones involved, not least including retinoids, progestins, and corticosteroids. Furthermore, apart from hormone messengers, there are many other signalling processes involved. This situation is further complicated by the fact that although chemicals can be shown to bind to certain receptors in test tube experiments, it is sometimes difficult to elucidate whether the adverse effects that they cause in animals are actually mediated primarily by the endocrine system. Exposures to ECDs
Wildlife will be especially vulnerable to the endocrine disrupting effects of pesticides,
because these chemicals are deliberately released into the environment. Effects linked to
endocrine disruption have been noted in invertebrates, reptiles, fish, birds, and mammals
living in polluted areas, but although most are linked to exposure to organochlorines, it is
always difficult to tie down particular causal agents with any certainty. Humans exposed
occupationally are also at increased risk, and there are studies linking exposure to pesticides
at work to impotence, reduced sperm counts, increased time to pregnancy, and increased
rates of birth defects in offspring. Similarly, in the Yaqui children in Mexico, who are highly
exposed to pesticides, developmental effects have been reported, and in women highly
exposed to DDT, shortened lactation has been noted.
The general public are exposed from residues in fruit and vegetables, and from
contaminated meat, fish, and dairy produce, due to the build up of persistent and
bioaccumulating pesticides in the food chain. Some hormone disrupting pesticides, such as
linuron and atrazine may also be found occasionally in drinking water.
Apart from the active ingredient, nonyl phenol ethoxylates may be used as the surfactant
in pesticides, and these can break down to nonyl phenol, an oestrogen mimic.
However, it is not only the effects due to any one particular spraying operation which give
rise to concern, the main worry is with the potential interactive effects of the numerous
hormone disrupting substances to which humans and wildlife are now exposed. Undertaking
risk assessment on single substances will not replicate the real world situation. It could
certainly be envisaged that exposure to oestrogen mimicking substances, anti-androgenic
substances, substances which inhibit the formation of steroids, and substances which
increase their clearance, could all give rise to an enhanced de-masculinising effect.
Recommendations for controls The possible additive or synergistic effects, and the need to review no observed effects levels (NOELs) with regard to endocrine effects, certainly provide a powerful argument for the implementation of larger safety factors if 'acceptable levels' of exposure to hormone disrupting substances are to be defined. This approach assumes, of course, that even for hormone disruptors acting as developmental toxins there is some biological threshold, and it would certainly be wiser to aim to eliminate exposures. Behavioural effects have been noted at low levels of exposure, and particularly taking into account the range of species upon which an ecosystem depends, it is doubtful if toxicity tests could be undertaken to pick up on all such potential effects, which could nevertheless have profound population level effects. Therefore, WWF UK believes that the goal should be to eliminate exposures to endocrine disrupting substances where possible. In particular, there should be a rapid move away from the use of endocrine disrupting pesticides that are also persistent and/or bioaccumulative. Table 1: Evidence of endocrine disrupting effects
Pesticide and usage
Human exposure routes
Atrazine A herbicide used on
non-crop land and in agriculture, water on occasion including, for example, weed control in maize (sweetcorn). Beta-HCH May be found as an
impurity in lindane. Also formed been found in rabbit imported as a by-product in the manufacture of lindane. UN ECE been found in meat and fish POP = P + B + T and butter oil. Also found in breast milk, - and still found in 1996/97 UK samples, although levels have decreased. Chlordane Mainly used to
lawns and gardens. Now widely oxychlordane the stable banned. UNEP POP = P + B + T metabolite. Due to atmospheric transport, Inuit women tend to have a diet highly contaminated with chlordane. Chlordecone (Kepone) Used to Exposure has occurred due to y* y*
including bananas and tobacco. animals. Has also been found Has also been used against ants in clams, and in breast milk. and cockroach. UN ECE POP = P + B + T DDT Banned in all countries for Residues found in beef (from
(tuna) and imported lamb's liver. Found in breast milk-and metabolites still found in UK samples, although declined since banned. Dicofol A non-systemic
organochlorine acaricide. Usage lemon products. Been found includes on cucumber, tomatoes, lettuce, ornamentals, body fat in US surveys in the hops, apples and strawberries. Can be contaminated with alpha-Cl-DDT. In EU, dicofol is not permitted if it contains less than 78% of pp dicofol or more Dieldrin Has been used as a
treatment. No longer produced. 1993 it was found in samples (NB. aldrin can break down to breast milk, and is still found in some UK samples, although levels have declined since usage was banned. Endosulfan A contact and
insecticide and acaricide, usage mange tout, tomatoes, and soft includes on hops, rape, several fruit, such as plums and soft fruits, and on ornamentals. Hexachlorobenzene HCB Was Found in rabbit from China.
used as a seed treatment and as Has also been found in earlier a fungicide, but is now banned in surveys of eels, meat, cow's several countries. Found as a picloram, and chlorthal-dimethyl samples although levels have (dacthal or DCPA). UNEP POP declined. = P + B+ T Lindane (Gamma-HCH) A
contact, ingested, and fumigant 75% of samples of chocolate organochlorine insecticide, used with a high cocoa butter on many crops including sugar used as a timber treatment, and mushrooms and in earlier in the home, for head lice. (now surveys in fish, meat, butter, banned for head lice in the vegetables, such as onions. Has also been found in cow's milk in the UK, although not detected in the latest survey in 1998. Still detected in some UK breast milk samples. Methoxychlor Insecticide used
on fruits, vegetables, forage crops and livestock. P + B Pyrethroids Insecticides widely When used for timber
The OSPAR document does not been found in rivers. specify which are believed to be EDCs. Toxaphene A mixture which
crops. Used to control ticks and toxaphene compounds. High mites in livestock. Now widely banned. UNEP POP = P + B + T mammals. Also found in Arctic and Baltic fish, such as salmon. In the 1980s was found in a survey of Swedish breast milk. Triazines Atrazine, simazine,
herbicides. The OSPAR document does not specify Tributyl tin Used as a biocide in Found in fish, and especially
plastic, paints and insulants. Has cooked on baking parchment. also been used in duvets. Human exposure does occur as butyltins have been found in human liver. Vinclozolin A dicarboximide
peas, turf and apple blossom. In usage. Also found in 1998 UK, some illegal usage on winter samples of kiwi fruit, lettuce. P + B peaches/nectarines, and tomatoes, and earlier samples of peas, peppers, orange, beans, cress, garlic, grape juice, salmon, and sultanas. A related anti-androgenic fungicide, procymidone has similarly been found in UK lettuce, and also in aubergines, peas, pears, wine and tomatoes. The y indicates endocrine disrupting effects Bioaccumulative (These symbols are used are as found in the OSPAR document DIFF as found in the OSPAR document); UNEP 99/3/20-E Rev. 1(L). They are not intended POPs are chemicals designated for inclusion to be exhaustive, but the * is used as found in the Convention and are therefore defined in the OSPAR document and denote 'and as P, B and T (toxic).; UN ECE POPs are others'. Some references may be incorrect, chemicals covered by the UN ECE Protocol but apart from those detailed for the on POPs and are therefore subject to pyrethroids, they are as stated in the atmospheric transport and are also defined as P + B + T (all UNEP POPs are also UN ECE POPs). vh = in vivo (relevant to vtw = in vitro (relevant vw = in vivo Table 2: WWF list of pesticides in the environment reported to have reproductive and/or endocrine disrupting effects Herbicides
2,4-D, 2,4,5-T, acetochlor, alachlor, amitrole, atrazine, bromacil, bromoxynil, cyanazine,
DCPA (dacthal), ethiozin, glufosinate-ammonium, ioxynil, linuron, metribuzin, molinate,
nitrofen, oryzalin, oxyacetmide/fluthamide (FOE 5043), paraquat, pendimethalin, picloram,
prodiamine, pronamide, simazine, terbutryn, thiazopyr, triclorobenzene, trifluralin
Fungicides
benomyl, etridiazole, fenarimol, fenbuconazole, hexachlorobenzene, mancozeb, maneb,
metiram, nabam, penachloronitrobenzene, pentachlorophenol, triadimefon, tributyltin,
vinclozolin, zineb, ziram
Insecticides
aldicarb, aldrin, bifenthrin, carbaryl, carbofuran, chlordane, chlordecone, chlorfentezine, 8-
cyhalothrin, DDT and metabolites DDE, DDD, deltamethrin, dicofol, dieldrin, dimethoate,
dinitrophenol, endosulfan (a and b), endrin, ethofenprox, fenitrothion, fenvalerate, fipronil,
a-HCH, heptachlor and H-epoxide, lindane (g-HCH), malathion, methomyl, methoxychlor,
mirex, oxychlordane, parathion (methylparathion), photomirex, pyrethrins, synthetic
pyrethroids, ronnel (fenchlorfos), toxaphene, transnonachlor
Nematicide
Rodenticide
Sources: 1. Colborn T, 1998, Endocrine disruption from environmental toxicant. In Rom W N (ed) Environmental and Occupational Medicine, Third edition, Lippincott-Raven Publishers, Philadelphia. 2. Brucker-Davis F, 1998, Effects of environmental synthetic chemicals on thyroid function, Thyroid 8(9), p827-856. 3. Short P, Colborn T, 1999, Pesticide use in the US and policy implications: a focus on herbicides, Toxicol Ind Healt

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