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briefing
paper
Mixed messages: pesticides
Pesticide Action Network UK
Mixed messages: pesticides
that confuse hormones
By Gwynne Lyons
◆ briefing 2 ◆ October 2000 ◆
M
any 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.
Pesticide Action Network UK
promotes healthy food,
sustainable agriculture and
a safe environment without
using hazardous pesticides
Pesticide Action Network UK
Eurolink Centre
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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 purpose 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
eThyroid
G neral
Sex
Pesticides
hormone
hormone
which
disruptors
affect
disruptors
steroid synthesis
Effects linked to
endocrine disruption
have been noted in
invertebrates, reptiles,
fish, birds, and
mammals living in
polluted areas.
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.
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 fertility4. 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 offspring5. 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 receptor6.
Anti-androgenic pesticides that bind to the androgen receptor include: the dicarboximide fungicides, vinclozolin7 and procymidone8; p'p'DDE9;
certain pyrethroids10; and the herbicide linuron11.
Researchers have evaluated the potency of the following pyrethroids in terms of their interaction
DDT is, however, still used in several tropical coun- with androgen binding sites, and in descending
tries. The challenge is for the global community to order this was: fenvalerate > phenothrin > fluvalifind other substances and regimes that are equally nate > permethrin > resmethrin12. In the case of
as efficacious in controlling malaria, and in this,
vinclozolin, it is the metabolites that are active
WWF is certainly playing an active part.
anti-androgens13.
Unfortunately, even where it is now banned, expo- The dose levels at which effects are noted are fairsure to DDT can still arise from a number of
ly low. For example, at a vinclozolin dose level of 3
sources including: mobilisation of existing body
mg/kg/day, male rats exposed in the womb were
burdens; from continued illegal usage; from sites
feminised, in that abnormal numbers of nipples
contaminated in the past; and from continued
were seen14. Similarly, at a dose level of 25 mg/ kg
usage elsewhere.
/day given from the fourteenth day of pregnancy
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
Humans exposed
occupationally are 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.
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-phenylphenol1,
DDT and metabolites (although the anti-androgenic properties of p'p'DDE may be of greater
importance); methoxychlor; chlordecone2; dieldrin, endosulfan; 1-hydroxychlordene (a metabolite of chlordane); and toxaphene (for relative
potencies see Soto el al3).
to three days after birth, procymidone caused
intersex characteristics in male rats, but these
workers did not determine a no-observed adverse
effect level15. 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 puberty16.
Pesticides which affect steroid synthesis
and metabolism
Numerous pesticides have been reported to affect
hormone synthesis and/or metabolism. These
include: the imidazole pesticides17 (such as propiconazole18, epoziconazole19 and ketoconazole20,21);
fenarimol22,23; TBT24; and several organochlorine
pesticides25.
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 activity26. Another pesticide, fenarimol,
is known to inhibit aromatase activity, and this has
also been shown to delay birth27. 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 wellknown 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 litre28
Thyroid hormone disruptors
Other pesticides can act on the thyroid. For example, the following substances can affect thyroid
Some of these can induce oestrogenic effects at
relatively low levels. For example, administration of hormone levels: amitrole29; ioxynil30; and the dithiocarbamates31 (such as maneb, mancozeb, and
methoxychlor to the new born rat at a dose level
2
Effects on the
Assessing
mode
brain
of action
zineb32). Amitrole (or aminotriazole) appears to
interfere with thyroid hormone synthesis and can
cause cancer of the thyroid33. 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 rats34,
and is believed to be an endocrine disruptor35,36,37.
Effects on the 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 birds38, and
similarly, carbamates have been associated with a
reduced number of eggs39. Also, in the males of
several animal species, certain organophosphates
and carbamates have been linked with effects on
sperm40. Some organophosphate pesticides have
been suggested to cause abnormal menses,
amenorrhea, and early menopause41, 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 semen42.
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 at
increased risk, and there are studies linking exposure to pesticides at work to impotence47.48,
reduced sperm counts,49,50 increased time to pregnancy51, and increased rates of birth defects in offspring.52,53,54 Similarly, in the Yaqui children in
Mexico, who are highly exposed to pesticides,
developmental effects have been reported55, and
in women highly exposed to DDT, shortened lactation has been noted.56,57
The general public are exposed to residues in
fruit and vegetables, and to 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 situaAldicarb, an extremely toxic systemic carbamate
insecticide, is also suspected of being an endocrine tion. It could certainly be envisaged that exposure
disruptor. When given to female pregnant rats at low to oestrogen mimicking substances, anti-androlevels of 1-100mg/kg, it has been shown to depress genic substances, substances which inhibit the
acetylcholinesterase activity more in the foetus than formation of steroids, and substances which
increase their clearance, could all give rise to an
in the mother43. It has also been suggested that
there may be a link between low level exposure and enhanced de-masculinising effect.
effects on the immune system44,45.
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.
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.
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'
Our knowledge of hormonal actions and receptor of exposure to hormone disrupting substances are
sites is also far from complete, and two receptors
to be defined. This approach assumes, of course,
for oestrogen have recently been identified. In
that even for hormone disruptors acting as develaddition, apart from the sex hormones and thyroid opmental toxins there is some biological threshhormones there are many other hormones
old, and it would certainly be wiser to aim to eliminvolved, not least including retinoids, progestins,
inate exposures. Behavioural effects have been
46
and corticosteroids . Furthermore, apart from
noted at low levels of exposure, and particularly
hormone messengers, there are many other sigtaking into account the range of species upon
nalling processes involved. This situation is further which an ecosystem depends, it is doubtful if toxicomplicated by the fact that although chemicals
city tests could be undertaken to pick up on all
can be shown to bind to certain receptors in test
such potential effects, which could nevertheless
tube experiments, it is sometimes difficult to eluci- have profound population level effects. Therefore,
date whether the adverse effects that they cause in WWF UK believes that the goal should be to elimianimals are actually mediated primarily by the
nate exposures to endocrine disrupting subendocrine system.
stances 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.
Wildlife will be especially vulnerable to the
endocrine disrupting effects of pesticides,
because these chemicals are deliberately
Exposures to ECDs
3
Table 1: Evidence of endocrine disrupting effects
Pesticide and usage
Human exposure routes
vth
vh
vtw
vw
Atrazine A herbicide used on non-crop land and in agriculture,
including, for example, weed control in maize (sweetcorn). Banned
for non-crop use in UK. P
Has been found in drinking water on occasion.
✓11
✓12*
✓13
Beta-HCH
Technical grade lindane, which may be used in some
countries, contains high levels of B-HCH (7-10%). Also formed as a
by-product in the manufacture of lindane. UN ECE POP = P + B + T
In the past, high levels have been found in rabbit imported from
China, and it has also been found in meat and fish and butter oil1.
Also found in breast milk, - and still found in 1996/97 UK samples,
although levels have decreased2.
✓14
✓15
Chlordane Mainly used to control termites, and on home lawns
and gardens. UN ECE POP = P + B + T
On occasion, has been found in breast milk, as has oxychlordane
the stable metabolite2. Due to atmospheric transport, Inuit women
tend to have a diet highly contaminated with chlordane3.
✓16
✓17
✓18
Chlordecone (Kepone) Used to control insects on crops,
including bananas and tobacco. Has also been used against ants
and cockroach. P + B
Exposure has occurred due to eating contaminated fish and animals. Has also been found in clams, and in breast milk4.
✓19* ✓20*
✓21
DDT
Banned in all countries for use in agriculture. Also used in
disease vector control (eg. malaria) - recommended for indoor spraying. UNEP POP = P + B + T
Residues found beef (from Brazil and Zimbabwe)5. In the past, found in rabbit (from
China)6 and in cow's milk and butter1. Also, in past has been found in fruits and vegetables (eg. citrus oils, courgettes, grapes, lettuce, mange tout, and sultanas)6.
Recently found in fish (tuna) and imported lamb's liver5. Found in breast milk-and
metabolites still found in UK samples, although declined since banned2.
✓11*, 23 ✓24, 25
Dicofol (Kelthane) A non-systemic organochlorine acaricide.
Usage includes on cucumber, tomatoes, lettuce, ornamentals, 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 than 1g/kg DDT and related compounds.
May be found in apples and lemon products5. Been found as a
contaminant in human body fat in US surveys in the 1980s2.
Dieldrin
Has been used as a sheep dip and in wood treatment.
No longer thought to be produced. (NB. aldrin can break down to
dieldrin). UNEP POP = P + B + T
A 1992 survey in the UK found very high levels in eels6. Also in 1993
it was found in samples of UK cow's milk and butter oil1. Dieldrin
has been found in breast milk, and is still found in some UK samples, although levels have declined since usage was banned2.
✓11* ✓29*
Endosulfan A contact and ingested organochlorine insecticide
and acaricide, usage includes on hops, rape, several soft fruits, and
on ornamentals. Widely used in developing countries. P + B
Residues have been found in 1998 UK samples of peas, mange
tout, tomatoes, and soft fruit, such as plums and blackcurrant5. In
the early 1990s, endosulfan was found in baby foods in the US2.
✓30
Hexachlorobenzene HCB
Used as a seed treatment and
as a fungicide, but is now banned in several countries. Found as a
contaminant of quintozene, tecnazene, chlorothalonil, picloram, and
chlorthal-dimethyl (dacthal or DCPA). UNEP POP = P + B+ T
Found in rabbit from China5. Has also been found in earlier surveys of eels6, meat, cow's milk and cheese1. HCB has also been
found in breast milk, and still found in some UK samples although
levels have declined2.
Lindane (Gamma-HCH) A contact, ingested, and fumigant
organochlorine insecticide, used on many crops including sugar beet
and oil seed rape. Also used as a timber treatment, and in the home,
for head lice. UNECE POP = P + B + T
A 1998 survey found lindane in 75% of samples of chocolate with a
high cocoa butter content5. Also found in 1998 samples of cereal
grains, and mushrooms5 and in earlier surveys in fish, meat, butter,
cheese, flour, bread and some vegetables, such as onions1. Has also
been found in cow's milk in the UK, although not detected in the latest
survey in 19981. Still detected in some UK breast milk samples2.
✓22
✓26, 27
✓28
✓18
✓31*
✓32
✓33
✓11
✓34*
✓15,
35-43
✓44*
Methoxychlor Insecticide used on fruits, vegetables, forage
crops and livestock. P + B
Pyrethroids
Insecticides. Permethrin also used for timber treatment. The OSPAR document does not specify which are believed to
be EDCs.
When used for timber treatment, exposure may occur via inhalation. Some have been found in rivers.
✓45
Toxaphene A mixture used as an insecticide, mostly on cotton
and other crops. Used to control ticks and mites in livestock. UNEP
POP = P + B + T
Due to atmospheric transport, Inuit women tend to have a diet highly
contaminated with toxaphene compounds. High levels found in
marine mammals3. Also found in Arctic and Baltic fish, such as
salmon8. In the 1980s was found in a survey of Swedish breast milk2.
✓30
Triazines Atrazine, simazine, cyanazine, amitrole and prometryn
are triazine herbicides. The OSPAR document does not specify
which are believed to be EDCs.
Like atrazine, simazine has occasionally been found in drinking
water.
Tributyl tin
Used as a biocide in antifouling paints, wood and
material preservatives, and in plastic, paints and insulants. Has also
been used in duvets.
Found in fish, and especially high levels were found in Baltic fish.5 Has
been found in food cooked on baking parchment. Human exposure
does occur as butyltins have been found in human liver10.
Vinclozolin A dicarboximide fungicide used on rape, beans,
peas, turf and apple blossom. In UK, some illegal usage on winter
lettuce. P + B
Residues found in UK lettuce in 1997 samples due to illegal usage.
Also found in 1998 samples of kiwi fruit, peaches/nectarines, and
tomatoes5, and earlier samples of peas, peppers, orange, beans,
cress, garlic, grape juice, salmon, and sultanas6. A related antiandrogenic fungicide, procymidone has similarly been found in UK
lettuce, and also in aubergines, peas, pears, wine and tomatoes5.
Notes to Table: P= Persistent B= Bioaccumulative (These symbols are used as found in the OSPAR
document); UNEP POPs are chemicals designated for inclusion in the Convention and are therefore
defined as P, B and T (toxic).; UN ECE POPs are chemicals covered by the UN ECE Protocol on POPs
and are therefore subject to atmospheric transport and are also defined as P + B + T (all UNEP POPs
are also UN ECE POPs).
vth = In vitro (relevant to humans)
vh = in vivo (relevant to humans)
✓17
✓18
✓46
✓47
✓48
✓49
✓13
The ✓ indicates endocrine disrupting effects are as found in the OSPAR document DIFF 99/3/20-E
Rev. 1(L). They are not intended to be exhaustive, but the * is used as found in the OSPAR
document and denote ‘and others’. Some references may be incorrect, but apart from those detailed
for the pyrethroids, they are as stated in the OSPAR document.
vtw = in vitro (relevant to wildlife)
4
vw = in vivo (relevant to wildlife)
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37. PB Singh, et al, Impact of c-HCH on sex
2,4-D, 2,4,5-T, acetochlor, alachlor, amitrole, atrazine, bromacil, bromoxynil,
steroid levels and their modulation by ovine
luteinizing hormone-releasing hormone and
cyanazine, DCPA (dacthal), ethiozin, glufosinate-ammonium, ioxynil, linuron,
Mystus gonadotropin in the freshwater catfish
metribuzin, molinate, nitrofen, oryzalin, oxyacetmide/fluthamide (FOE 5043), paraquat,
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Gwynne Lyons is the Toxics and Policy
Advisor to WWF-UK
Please contact PAN UK for more
information about this briefing