Extracts from: TOXICOLOGICAL PROFILE FOR PYRETHRINS AND PYRETHROIDS
(September 2003, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public Health Service, Agency
for Toxic Substances and Disease Registry) in Relation To My & My Son's Pesticide Poisoning
Symptoms & Current Chemical Sensitivities
Murray Thompson – June 2000
This document is a revised version of one
sent to Wentworth Area Community Housing. Unlike some statements made by
some pesticide
contractors and various 'authorities', this document demonstrates clearly that pesticides containing
Bifenthrin and other pyrethroids are extremely TOXIC. Community Housing (CH) need to seriously
evaluate this information and generate a more sophisticated appreciation and
model for their engagement of the concept of Duty of Care. Because, if CH, the pest contractors, and CH
tenants are not aware of this information, then everyone is flying blind!
Note that:
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I have yellow highlighted and in some cases further bolded and enlarged some text within the document that informs specifically regarding important pyrethroid toxicities, including Bifenthrin (used in flea treatments). Although I have left in surrounding text for the sake of transparency, context and broader understanding, the reader can skip to the highlighted text areas and very quickly gain an appreciation of the true toxicological profile for these pesticide mixtures.
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For clarity I have placed some basic information on Pyrethroids re Overview and Chemical Identity out of sequence. Other quotes may be grouped out of sequence.
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CH should ensure their insurance regarding sub-contractors is firmly in place in terms of the possibility of future litigation arising from pesticide injury in their tenants. The NSW Department of Housing (DOH) has recently been on a steep learning curve regarding this issue through my legal action against them.
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Bifenthrin is a Type I pyrethroid.
6.1 OVERVIEW
Synthetic
pyrethroids are a diverse class of over 1,000 powerful insecticides that are
structurally similar to the pyrethrins (Mueller-Beilschmidt 1990). Although they are based on the chemical
structure and biological activity of the pyrethrins, the development of
synthetic pyrethroids has involved extensive chemical modifications that make
these compounds more toxic and less degradable in the environment.
p.165
4. CHEMICAL AND PHYSICAL INFORMATION
4.1 CHEMICAL IDENTITY
The
naturally-occurring pyrethrins, extracted from chrysanthemum flowers, are
esters of chrysanthemic
acid (Pyrethrin I,
Cinerin I, and Jasmolin I) and esters of pyrethric acid (Pyrethrin II, Cinerin
II, and
Jasmolin II). In the United States, the pyrethrum extract is
standardized as 45–55% w/w total pyrethrins.
The typical proportion of Pyrethrins I to II is 0.2:2.8, while the ratio
of pyrethrins:cinerins:jasmolins
is 71:21:7 (Tomlin
1997). Information regarding the chemical identity of the pyrethrins is
presented in
Table 4-1.
Pyrethroids are
synthetic esters derived from the naturally-occurring pyrethrins. One exception to the
axiom that all
pyrethroids are esters of carboxylic acids is noteworthy. There is a group of oxime ethers
that exhibits
insecticidal activity similar in nature to the pyrethrins and pyrethroid esters
(Davies 1985). Little data exist
regarding these compounds, and no commercial products have been produced. Commercially available pyrethroids include
allethrin, bifenthrin,
bioresmethrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin,
esfenvalerate (fenvalerate), flucythrinate, flumethrin, fluvalinate, fenpropathrin,
permethrin, phenothrin, resmethrin, tefluthrin, tetramethrin, and tralomethrin. Information regarding the chemical identity
of pyrethroids is shown in Table 4-2.
With the exception
of deltamethrin, pyrethroids are a complex mixture of isomers rather than one
single pure compound. For pyrethroids
possessing the cyclopropane moiety, isomerism about the cyclopropane ring
greatly influences the toxicity of these insecticides. The presence of two chiral centers in the ring
results in two pairs of diastereomers. The diastereomers and their nonsuperimposable
mirror images (enantiomers) are illustrated in Figure 4-1. In this figure, the
C-1 position of the ring is assigned to the carbon atom bonded to the ester
moiety. It is also customary to
designate the stereochemistry at the C-3 position as simply cis or trans
relative to the ester group bonded to C-1 rather than assigning its absolute configuration.
The 1R conformations about the
cyclopropane ring are considerably more toxic than the 1S isomers. Both the cis and trans isomers show
insecticidal activity, but have differing mammalian toxicities, with the cis
isomers being more potent (Ray 1991). Pyrethroids
that contain a cyano substituent at the alcohol moiety (Type II pyrethroids)
demonstrate differing toxicity based upon the optical isomerism of the alpha
carbon. It has been demonstrated that the S conformation about the alpha carbon
is considerably more toxic towards insects when compared to the R conformation
(Dorman and Beasley 1991). Figure 4-2
illustrates the S conformation of the type II pyrethroid cyhalothrin about the alpha
carbon. Pyrethroids such as cyfluthrin,
cypermethrin, and cyhalothrin possess three chiral centers, and thus consist of
eight possible isomers. The production
of pyrethroids with differing isomeric ratios is one reason for the wide
variation in reported toxicities of these compounds. For example, cypermethrin is formulated as
four different insecticides (alpha-, beta-, theta- and zeta-cypermethrin)
depending upon the ratio of the different isomers; and each of these products
has different toxicologic properties. The
complex compositions of several important pyrethroids are illustrated in Table
4-3.
pp. 131-141
3.2.1 Inhalation Exposure
3.2.1.3 Immunological
and Lymphoreticular Effects
Hypersensitivity pneumonitis, characterized by pleuritic chest pain, nonproductive cough, and shortness of breath, was diagnosed in a 24-year-old woman who was hospitalized for 2 weeks following repeated indoor use of a pyrethrum-based insecticide (Carlson and Villaveces 1977). In this patient, levels of antibodies IgG, IgM, and IgE were all elevated. Symptomatic treatment was employed, and a week after discharge, a pulmonary challenge test to the insecticide resulted in an itchy and runny nose within 2 minutes following initiation of exposure, but no cough or shortness of breath. Subsequent skin tests resulted in immediate skin reactions and allergic pulmonary response to pyrethrum, but not to other ingredients in the insecticide. In a review of literature pertaining to pyrethrum (Moore 1975), it was noted that many individuals who were sensitive to ragweed were also sensitive to pyrethrum, but that the sensitization effect arose mainly from a volatile oil contained in the pyrethrum extract, not from the pyrethrins. On the other hand, pyrethrins were implicated in two cases of severe asthmatic reactions to exposure to dog shampoo products containing pyrethrins (Wagner 2000; Wax and Hoffman 1994). A 45-year-old female animal keeper, who was suspected to be suffering from pesticide intoxication, indicated that she had been exposed to pyrethroid insecticides over a period of 13 years (Mitsche et al. 2000). Upon skin (scratch) testing, dose-dependent allergic responses (wheals and flares) were elicited from the Type I pyrethroids, S-bioallethrin and permethrin.
3.2.1.4 Neurological
Effects
Shortness of breath, nausea, headache, and irritability were experienced by five office workers upon entering their work area 2 days after it had been sprayed with cypermethrin in an effort to eliminate termites (Lessenger 1992). The symptoms were exacerbated when the air-conditioning system was activated to ventilate the area, but levels of cypermethrin in the air were not measured. Signs of neurotoxicity have been associated with acute occupational (inhalation and dermal) exposure to various pyrethroids during outdoor or indoor spraying (Chen et al. 1991; He et al. 1991; Moretto 1991; Shujie et al. 1988; Zhang et al. 1991). In a cross-sectional survey on the prevalence of acute pyrethroid poisoning of cotton workers conducted in China in 1987 and 1988 (Chen et al. 1991), approximately 27% (696 of 2,588) of the workers who sprayed pure pyrethroids reported having experienced symptoms such as abnormal facial sensations (paresthesia), dizziness, headache, nausea, loss of appetite, blurred vision, and tightness of the chest. Eight of these workers were diagnosed with mild acute pyrethroid poisoning, characterized in part by listlessness and muscular fasciculations. He et al. (1991) reported increased peripheral nerve excitability in cotton workers following 3 days of exposure to deltamethrin during spraying. Nerve excitability was assessed by presenting two sequential electrical stimuli of equal intensity and duration to the median nerve area of the wrist and recording the median nerve activity at the lateral side of the elbow. Following deltamethrin exposure, median nerve conduction measurements revealed a significant increase in the supernormal period, defined as a period after recovery of normal excitability (from a given action potential) during which an action potential induced by a second stimulus is higher in amplitude than the first action potential. In some of these studies, air concentrations of pyrethroids in the breathing zone of the sprayers were measured and ranged from approximately 0.005 to 2.0 μg/m3. However, one study reported air concentrations as high as 24 μg/m3 (Shujie et al. 1988). Among sprayers, dermal contact was considered to be the major source of exposure, although some of the sprayers also reported symptoms of nasal and laryngeal irritation (Moretto 1991). Facial paresthesia, dizziness, fatigue, miliary red facial papules, and sniffles and sneezes were noted in subjects exposed to deltamethrin and fenvalerate while packaging the insecticides (He et al. 1988). Air sampling indicated pyrethroid levels in the range of 0.005–0.055 mg/m3, but dermal contact was also evident, and may have been the basis for increased signs of toxicity during summer months.
p.29-30
In studies of acute lethality associated with inhalation exposure to pyrethrins or pyrethroids, neurological effects were observed at or near lethal exposure levels. However, most studies do not include dose response data for exposure levels much lower than those resulting in death. Tremors were observed in rats acutely exposed to pyrethrins at mean analytical airborne concentrations $2,100 mg/m3, but not at a concentration of 690 mg/m3 (Schoenig 1995). Acute exposure of rats to aerosols of a 13% formulation of cyhalothrin, at analytical concentrations ranging from 3.6 to 68 mg/m3, resulted in dose-related increasing severity of neurological signs, ranging from temporary lethargy, abnormal posture, and salivation at the lowest concentration, to convulsions and death within 15 minutes postexposure at the highest concentration (Curry and Bennett 1985). Disturbed posture and abnormal motor activity were observed in rats exposed to aerosols of cyfluthrin for 4 hours at an analytical concentration of 17 mg/m3, the lowest level presented. A concentration of 735 mg/m3, which was lethal to many of the rats, caused severe behavioral disturbances in surviving rats that continued for 3 days postexposure (Pauluhn and Thyssen 1982). A group of female rats exhibited no signs of toxicity in response to acute exposure to cyfluthrin at an analytical concentration of 44 mg/m3 (Flucke and Thyssen 1980). Both male and female rats, similarly exposed to a concentration of 57 mg cyfluthrin/m3, showed signs of restlessness and altered gait. Labored breathing, hyperactivity, and tremors were reported in rats repeatedly exposed (6 hours/day, 5 days/week for 90 days) to pyrethrins at a mean airborne concentration of 356 mg/m3 (Schoenig 1995). Repeated 6-hour inhalation exposures to atmospheres containing cyfluthrin concentrations of 10.5 mg/m3 or higher resulted in dose-related unspecified clinical signs of behavioral disorders (Flucke and Thyssen 1980; Thyssen 1980).
pp.29-31
In this following section (3.2.2), oral
exposure to pyrethroid and/or pesticide mixture carrier/‘inerts’ solvents
cannot be ruled out in my & my son's original poisoning case because
studies show that even outdoor pyrethroid treatments (which was the case with
my unit’s termite treatment in 2000) can result in the deposition of pyrethroid
indoors. In terms of the recent (Thursday 23 April 2009) flea
treatment in McQuade Avenue, pyrethroid was apparently sprayed internally, so
residents will have been exposed to Bifenthrin dermally, via inhalation and orally
from spray residues settling on food preparation surfaces.
3.2.2 Oral Exposure
3.2.2.2
Systemic Effects
Hepatic Effects. No studies were located regarding hepatic effects in humans
following oral exposure
to pyrethrins or pyrethroids. Some animal studies indicated increased liver
weights, congestion,
hepatocellular hypertrophy, and
other microscopic signs of liver changes in laboratory animals during
intermediate- and chronic-duration
oral exposure to pyrethrins or pyrethroids, particularly at dose levels
also resulting in clinical signs of
neurotoxicity (Hext et al. 1986; IRIS 2003d, 2003e; Ishmael and
Litchfield 1988; Parker et al.
1984a, 1984b; Schoenig 1995). Increased
liver enzyme activity has also
been observed in some animal studies
(EPA 1985a, 1985b, 1994c; Schoenig 1995). These hepatic effects
may reflect, at least in part, an
adaptive response similar to that seen following exposure to many other
xenobiotics (Ishmael and Litchfield
1988; Okuno et al. 1986a). Increased
liver weight and liver
discoloration were noted in mice fed
pyrethrum extract in the diet for 18 months at concentrations
resulting in doses of total
pyrethrins of approximately 346 and 413 mg/kg/day in males and females,
respectively.
The male mice also exhibited vacuolar
fatty liver changes (EPA 1994c).
Endocrine
Effects. No studies were located regarding
endocrine effects in humans following oral
exposure to
pyrethrins or pyrethroids. Limited data
were available regarding endocrine effects in animals following oral exposure
to pyrethroids. Serum levels of the thyroid hormones T3 and T4 were
significantly decreased in mice administered
fenvalerate at a dose level of 120 mg/kg/day for 15 days
(Maiti and
Kar 1998). Akhtar et al. (1996) reported similar effects in rats
administered bifenthrin or
lambda-cyhalothrin
at daily oral dose levels of 0.5 mg/rat (approximately 0.75 mg/kg/day) and 0.2
mg/rat (approximately 2 mg/kg/day), respectively, for 21 days. Lambda-cyhalothrin treated rats also exhibited a significantly
decreased serum T3/T4 ratio, relative to controls. In addition, both bifenthrin and lambdacyhalothrin treatment resulted in
significantly increased serum TSH levels, compared with control rats. The studies of Maiti and Kar (1998) and
Akhtar et al. (1996) did not include dose-response information, nor were
thyroid tissues examined. However, these studies indicate
that pyrethroids may exert a direct or indirect influence on the thyroid.
pp.54-55
3.2.2.3
Immunological and Lymphoreticular Effects
Information on immunotoxicity of
selected pyrethroids is available from oral studies in rats, mice, and
rabbits repeatedly administered
pyrethroids at doses low enough that clinical signs of neurotoxicity were not
observed (Blaylock et al. 1995; Demian 1998; Demeans and El-Sayed 1993; Dési et
al. 1986;
Lukowicz-Ratajczak and Krechniak
1992). Dési et al. (1986) conducted a
series of studies in rats and
rabbits. In rats, a single oral dose of cypermethrin
at 125 mg/kg resulted in statistically significant
changes, which included suppression
of the humoral immune response, decreases in rosette-forming
lymphocytes and ratio of lymphocytes
to leukocytes, and decreased relative spleen weight. Although
doses of cypermethrin at 6.25, 12.5,
or 25 mg/kg/day for 6 or 12 weeks did not result in significant
changes in relative spleen weight, a
significantly reduced humoral immune response was observed at the 25 mg/kg/day
dose level, and both the 12.5 and 25 mg/kg/day levels resulted in significant
decreases in rosette-forming lymphocytes.
Dose-dependent significant suppression of the humoral immune response in
rabbits was observed by the end of week 1 of a study in which cypermethrin was
administered orally to rabbits 5 days/week for 6 weeks at levels of 75, 150, or
300 mg/kg/day.
p.57
3.2.2.4
Neurological Effects
Some investigators have assessed other aspects of
neurotoxicity in animals administered oral doses of
pyrethroids, often at doses much lower than those
resulting in typical clinical signs. For
example, Crofton and Reiter (1988) observed significant decreases in motor
activity of rats following administration of a Type I pyrethroid (permethrin) at 200 mg/kg and Type II
pyrethroids (cyfluthrin at 12.5 mg/kg, fenvalerate at 30 mg/kg, flucythrinate
at 2.5 mg/kg, cypermethrin at 30 mg/kg, fluvalinate at 15 mg/kg, and a
pyrethroid identified as RU26607 at 3 mg/kg). Crofton and Reiter (1988) also found that some
of the pyrethroids tested affected the acoustic startle response by altering
the amplitude or latency. In another rat study, a Type I
pyrethroid (NAK 1901) enhanced the acoustic startle response amplitude in a dose-dependent
manner, whereas a Type II pyrethroid (cypermethrin) had no effect on
amplitude or latency, even at a dose level that elicited clinical signs (Hijzen
et al. 1988). Hypersensitivity to sound
was noted in some rats administered cypermethrin in the diet at a concentration
resulting in daily intakes of 27 mg/kg for 83 days (EPA 1992c)…
Husain et al. (1991) observed pronounced
treatment-related changes in brain levels of the neurotransmitters
noradrenaline and dopamine, as well as their acid metabolites, following oral
administration of fenvalerate at doses of 5–20 mg/kg/day for 21 days. The changes did not appear to be either
dose-related or region specific, although the brain regions most affected
appeared to be those that contribute most significantly to motor function and
aggression. Significant increases were
noted in grouped total activity and individual nonambulatory (but not ambulatory)
activity of male mice observed for 4 hours following single oral administration
of permethrin at 50 mg/kg or fenvalerate at 30 mg/kg (Mitchell et al. 1988). These effects were observed in the absence of
typical clinical signs of pyrethroid-induced neurotoxicity.
p.60
3.2.2.5
Reproductive Effects
Some investigators have reported adverse effects in
male reproductive organs following intermediate duration oral exposure to
pyrethroids at dose levels below those eliciting clinical signs of
neurotoxicity. Abd El-Aziz et al. (1994)
reported that male rats, administered deltamethrin in oral doses as low as 1
mg/kg/day (the lowest level tested) for 65 days, exhibited significantly lower
weights of testicles, seminal vesicles, and prostate gland than vehicle
controls. Sperm analysis of treated rats
revealed significantly reduced sperm cell concentration, live cell percentage,
and motility index, and a significantly higher percentage of total sperm
abnormalities, relative to controls. Plasma
testosterone levels were significantly reduced as early as 14 days following
the beginning of treatment, remaining significantly lower 21 days after
treatment ceased. Male fertility was
tested at the end of treatment and 60 days posttreatment. At both time points, the percentage of
successful matings to untreated female rats was 50% that of controls.
Similarly, oral administration of cypermethrin to
male rats at 3.8 and 7.7 mg/kg/day (El-Khalek et al.
1999) and fenvalerate at 20 or 100 mg/kg/day (Hassan
et al. 1993) for 65 days resulted in reduced male
reproductive organ weights and significantly altered
sperm characteristics.
pp.61-62
3.2.3 Dermal
Exposure
3.2.3.4
Neurological Effects
Paresthesia (an
abnormal cutaneous sensation sometimes described as tingling, burning,
stinging,
numbness, and itching) has been widely reported
among individuals occupationally exposed to
pyrethroids (Flannigan and Tucker 1985; Flannigan et al. 1985b; Knox et al. 1984;
LeQuesne and
Maxwell 1980; Tucker
and Flannigan 1983; see also Vijverberg and van den Bercken 1990 for a
summary of available
information on occupationally-induced paresthesia)…
Signs of mild acute pyrethroid poisoning include
dizziness, headache, and nausea, in addition to
paresthesia. These
signs have been associated with acute occupational (inhalation and dermal)
exposure to various pyrethroids during outdoor or indoor spraying (Chen et al. 1991; Moretto 1991;
Shujie et al. 1988; Zhang et al. 1991)…
Although dermal exposure was considered to be the major source of
exposure, inhalation exposure was also likely. Facial paresthesia, dizziness, fatigue, miliary
red facial papules, and sniffles and sneezes were noted in subjects exposed to deltamethrin
and fenvalerate while packaging the insecticides (He et al. 1988). Both inhalation and dermal exposures were
likely, although increased toxicity during summer months was indication that dermal
exposure may have been increased when greater areas of skin were exposed due to
warmer weather.
p.68-69
3.3
GENOTOXICITY
In vitro experiments in mammalian cells
show a greater percentage of mutagenic effects than the bacteria and yeast
studies (Tables 3-6 and 3-7). Investigations
of human, pig, and cattle lymphocytes, Chinese and Syrian hamster cells, and
mouse spleen cells were positive for several genetic end points. Chromosomal aberrations, sister chromatid
exchange, increased micronuclei, DNA damage, C-mitosis induction, and other
damage were all observed. However, as
with the bacteria studies, no consistent pattern was seen that could relate
genotoxicity to the presence or absence of metabolic activation of the pyrethroids
by liver cells or enzymes.
3.4
TOXICOKINETICS
3.4.1.1 Inhalation Exposure
Several studies demonstrate absorption of Type I and Type II pyrethroids following occupational
exposure through identification of pyrethroid metabolites in urine (Aprea et al. 1997; Chester et al. 1987, 1992; Kühn et al. 1999; Leng et al. 1996, 1997b). In some cases, plasma levels of pyrethroids were below the limits of detection (5 μg/L) (Leng et al. 1997a, 1997b). Absorption of cyfluthrin in workers was confirmed by measurement of plasma cyfluthrin levels, although estimates of total exposure levels of cyfluthrin in these workers were not available (Leng and Lewalter 1999). It appears that pyrethroids are rapidly absorbed following inhalation, based on the appearance of urinary metabolites within 30 minutes of exposure (Leng et al. 1997a). In this study, an increase in the amount of urinary metabolites correlated with increasing exposure levels, indicating that absorption by the inhalation route is not capacity-limited, at least over the range of exposures studied (10–160 mg/m3). However, occupational exposure of humans to pyrethroids may include inhalation, oral, and/or dermal routes…
p.84
3.4.2
Distribution
No information is available regarding the distribution of Type I and Type II pyrethroid compounds or
pyrethroid metabolites in humans, except for information regarding the distribution of pyrethroids and
pyrethroid metabolites into excretory compartments. Given the lipophilic nature of pyrethroids, it is
expected that, in humans, they are widely distributed and undergo rapid distribution to tissues with a high lipid content, including fat and central and peripheral nervous tissues. Based upon observations of central and peripheral nervous system toxicity in humans exposed to pyrethroid compounds, it is apparent that distribution of pyrethroids to these tissues occurs (Aldridge 1990; Casida et al. 1983; Vijverberg and van den Bercken 1990). Since pyrethroid metabolites are less lipid soluble than the parent compounds, it is expected that distribution of metabolites to central and peripheral nervous tissues would be decreased compared to that of the parent compounds. Studies in several mammalian species confirm that pyrethroids are widely and rapidly distributed to many tissues, including liver and kidney, and are concentrated in central and peripheral nervous tissues.
p.87
3.4.2.4 Other
Routes of Exposure
No information was located regarding distribution of pyrethroids in humans following exposure by other
routes. Following intravenous administration in rats, Type I and Type II pyrethroids are rapidly and widely distributed to tissues and are concentrated in nervous tissue (Anadón et al. 1991b, 1996; Gray and Rickard 1982; Gray et al. 1980a; Silver and Dauterman 1989a). Plasma levels of parent compound exhibit a biphasic decline and fit a two-compartment model with rapid distribution phase (Anadón et al. 1991b, 1996). Distribution to the central nervous system is very rapid, with concentrations reaching peak levels within 5 minutes of administration (Gray et al. 1980a). Following intraperitoneal injection of rats with Type I pyrethroids, pyrethroids are rapidly distributed to the liver and are found to be associated with several subcellular fractions, including microsomes, indicating that pyrethroids are rapidly distributed to a detoxifying organ (Graillot and Hoellinger 1982). Results of these studies provide supportive evidence for the expectedly rapid and wide distribution of pyrethroids after absorption in humans.
3.4.3 Metabolism
Extensive study of the metabolic pathways involved in the biotransformation of pyrethroids in humans
has not been undertaken. Information on the metabolism of Type I and Type II pyrethroid compounds in humans is based upon identification of pyrethroid metabolites in urine and blood obtained in a small
number of studies conducted under controlled conditions or following occupational exposures. In
contrast, the metabolism of Type I and Type II pyrethroid compounds has been extensively studied in
several mammalian animal models. Since the metabolites that have been identified in humans have also been identified in other mammalian species, it is unlikely that there are significant qualitative differences between humans and other mammals in the major metabolic pathways for pyrethroids, although some species differences do undoubtedly exist (Anadón et al. 1991b; Eadsforth and Baldwin 1983; Eadsforth et al. 1988; Elliott et al. 1976; Gaughan et al. 1977; Leng et al. 1997a, 1997b; Woollen et al. 1992). The following summary of pyrethroid metabolism is based on the results of extensive investigations of the metabolism of pyrethroids in mammalian models. It is presumed that these metabolic pathways pertain to human metabolism of pyrethroid compounds, although there may be important quantitative differences between species.
All synthetic pyrethroid compounds appear to be degraded by similar metabolic processes in mammals.
Upon administration of pyrethroids to mammals, biotransformation takes place through hydrolysis of the central ester bond, oxidative attacks at several sites, and conjugation reactions to produce a complex array of primary and secondary water-soluble metabolites that undergo urinary and biliary excretion (Casida et al. 1983; Gray and Soderlund 1985; Leng et al. 1999a). It is widely accepted that metabolism results in the formation of compounds that have little or no demonstrable toxicity, although the formation of reactive or toxic intermediates cannot be ruled out, and it appears that cleavage of the ester bond results in substantial detoxification (Gray and Soderlund 1985; Hutson 1979). For halogenated pyrethroids (such as cyfluthrin, cypermethrin, and permethrin), rapid hydrolytic cleavage of the ester bond is followed by oxidation to yield carboxylic acid derivatives and phenoxybenzoic acid derivatives (Leng et al. 1997a, 1997b). These metabolites are, in general, excreted as alcohols, phenols, carboxylic acids, and their glycine, sulfate, glucuronide, or glucoside conjugates (Aprea et al. 1997; Casida et al. 1983). Metabolic pathways for permethrin, cypermethrin, and deltamethrin are shown in Figure 3-3. However, depending upon the type of pyrethroid compound, either oxidation or hydrolysis may predominate (Miyamoto 1976). The presence of the alpha-cyano group of the Type II pyrethroid compounds has been shown to decrease the rate of hydrolytic cleavage of the ester bond (Casida et al. 1983). Many of the trans enantiomers of pyrethroid compounds are metabolized mainly through hydrolytic cleavage of the ester linkage, with subsequent oxidation and/or conjugation of the component alcohol and acid moieties, whereas certain cis enantiomers are more resistant to hydrolytic attack and are degraded via oxidation at various sites of the molecule (Miyamoto 1976; Shono et al. 1979). For pyrethroids containing an alpha-cyanophenoxybenzyl substituent (Type II pyrethroids), cleavage of the ester bond results in the release of cyanide, which is rapidly converted mainly to thiocyanate (Casida et al. 1983; Gray and Soderlund 1985; Ohkawa et al. 1979). It does not appear that there is significant additional metabolic fragmentation of the acid and alcohol moieties, since metabolism studies with 14C-labeled pyrethroid compounds yield little or no detectable 14CO2 (Ohkawa et al. 1979; Ruzo et al. 1978).
Information on the specific enzymes involved in the metabolism of pyrethroid compounds is limited.
Metabolism appears to involve nonspecific microsomal carboxyesterases and microsomal mixed function oxidases, which are located in nearly all tissue types (Casida et al. 1983; Miyamoto 1976; Shono et al. 1979). Since microsomal enzymes play an important role in the metabolism of pyrethroids, it is expected that many tissue types are potentially capable of rapidly metabolizing these compounds, with a particularly important role for the liver. Pyrethroids are metabolized in blood in vitro (Gray and Rickard 1982). Metabolism of pyrethroids may also occur in the brain (Anadón et al. 1996; Ghiasuddin and Soderlund 1984), which may contribute to the detoxification of some pyrethroids in mammals (Ghiasuddin and Soderlund 1984). Information on the effects of induction or inhibition of microsomal enzymes by other chemicals or drugs on the rate of metabolism of pyrethroid compounds in humans or animals was not identified. No information was located regarding sex- or age-related differences in metabolism of pyrethroids following exposure in humans or animals.
3.5
MECHANISMS OF ACTION
3.5.2
Mechanisms of Toxicity
The
primary site of action for pyrethrins and pyrethroids is the sodium channel of
nerve cells, as is also
the
case for DDT and its analogs (for reviews, see Cassida et al. 1983; Coats 1990; Narahashi 1985;
Sattelle and
Yamamoto 1988; Soderlund 1995; Soderlund et al. 2002; Valentine 1990;
Vijverberg and van
den Bercken 1990). Using a variety of methods, including voltage
clamp and patch clamp techniques, it
has been shown that
pyrethrins and pyrethroids slow the closing of sodium channel gates following
an
initial influx of
sodium during the depolarizing phase of an action potential, which results in a
prolonged
sodium tail current
(Narahashi 1986; Vijverberg and Van den Bercken 1982). Two different types of
pyrethroids are
recognized, based on differences in basic structure (the presence or absence of
a cyano
group in the alpha
position), and the symptoms of poisoning (Coats 1990; Verschoyle and Aldridge
1980). Type I pyrethroids do not include a cyano group; their effects in
rodents typically include rapid
onset
of aggressive behavior and increased sensitivity to external stimuli, followed
by fine tremor,
prostration
with coarse whole body tremor, elevated body temperature, coma, and death. The term
T-syndrome (from
tremor) has been applied to Type I responses. Type II pyrethroids include a cyano group;
their effects in rodents are usually characterized by pawing and burrowing
behavior, followed by profuse salivation, increased startle response, abnormal
hindlimb movements, and coarse whole body tremor that progresses to sinuous
writhing (choreoathetosis). Clonic
seizures may be observed prior to death. Body temperature is not increased, but may
decrease. The term CS-syndrome (from choreoathetosis
and salivation) has been applied to Type II responses. Two of the cyano-pyrethroids, fenpropathrin
and cyphenothrin, have been shown to trigger responses intermediate to those of
T-syndrome and CS-syndrome, characterized by both tremors and salivation
(Miyamoto et al. 1995; Wright et al. 1988). Mechanisms underlying this intermediate
response type have not been elucidated. Occupational
exposure to pyrethroids (particularly Type II pyrethroids containing the cyano
group) frequently leads to paresthesia (abnormal cutaneous sensations such as
tingling, burning, numbness, and itching). This response is considered to be the result
of the direct action of pyrethroids on sensory nerve endings (LeQuesne and
Maxwell 1980; Wilks 2000), causing repetitive firing in these fibers
(Vijverberg and van den Bercken 1990).
p.103-104
Marked differences
exist in the duration of action on the sodium channel gate, particularly
between
Type I and Type II
pyrethroids. These differences may
account for the differences observed in toxic
effects elicited in
laboratory animals. Measurements of
sodium tail currents in frog nerve fibers treated
with Type I
pyrethroids measure approximately 6–150 milliseconds in duration, whereas those
generated from Type II pyrethroids last much longer (290 milliseconds to as
long as several seconds) (Narahashi 1986; Vijverberg et al. 1986). The shorter-duration sodium tail current
generated by Type I pyrethroids results in an elevated after potential that may
cause repetitive discharges. The
longer-duration sodium tail current generated by Type II pyrethroids may result
in summation of after potentials, which can cause gradual depolarization of the
nerve and frequency-dependent suppression of action potentials. For both Type I and Type II pyrethroids, the
magnitude of effect on sodium influx is strongly dependent on temperature,
increasing markedly with cooling (Narahashi 1971, 1976; Vijverberg et al.
1983). The action of pyrethroids on as little as 0.6% of the
sodium channel gates results in repetitive after-discharges that could lead to
neurotoxic symptoms in animals (Narahashi 1996; Song and Narahashi
1996).
p.104
Pyrethroids appear
to bind to the membrane lipid phase in the immediate vicinity of the sodium
channel, thus modifying the channel kinetics. Results of radioligand binding assays indicate
that the actions of DDT and pyrethroids on the sodium channel are
site-specific, functionally distinct from, but allosterically coupled to, sites
2, 3, and 5 of the 5 known neurotoxin-binding domains of the sodium channel
(Lombet et al. 1988). Pyrethroids do not
appear to influence sodium channel properties such as cation selectivity and
cation binding (Yamamoto et al. 1986). Stereochemistry
dictates the degree of toxicity that will be expressed by a given pyrethroid
formulation or mixture. In the case of
tetramethrin, like all other Type I pyrethroids, the 1R conformation is considerably
more toxic than the 1S conformation. The
1S isomer can also inhibit toxicity by competitive inhibition at a number of
stereospecific pyrethroid binding sites, thus preventing binding of the more toxic
1R isomer (Narahashi 1986). Furthermore,
it has been observed that the cis isomers possess greater mammalian toxicity
than the trans isomers. For these reasons, recent formulations of tetramethrin (d-tetramethrin)
contain predominantly the 1R cis and 1R trans isomers in a ratio of 20:80
(Tomlin 1997).
Type II pyrethroids
have been shown to inhibit specific binding at or near the picrotoxin site of
GABAA
receptors in mouse
brain (Crofton et al. 1987; Lawrence and Casida 1983), specifically inhibiting
GABAdependent chloride flux (Bloomquist et al. 1986). However, taken together, the results of a
number of studies that investigated the actions of pyrethrins and pyrethroids
on ligand-gated ion channels indicate a limited role for the GABAA receptor in
pyrethroid-induced neurotoxicity (Bloomquist 1993). Recently, Forshaw et al. (2000) demonstrated
that voltage-gated chloride channels may play a role in Type II, but not Type
I, pyrethroid poisoning. Their patch
test experiments showed that ivermectin and pentobarbitone significantly
increased open chloride channel probability in mouse neuroblastoma cells. When rats were pretreated with ivermectin or
pentobarbitone and subsequently administered the Type II pyrethroid
deltamethrin, comparatively reduced severity of neurotoxic effects was
observed. This was an indication that
these chemicals effectively antagonized Type II pyrethroid poisoning. Changes in neurotoxic effects were not
observed when the Type I pyrethroid, cismethrin, was used. Other pyrethroid-induced effects include altered concentrations of
catecholamines, blood glucose, and lactate, and marked changes in cerebral
blood flow. However, these effects may be
secondary effects arising from neural dysfunction resulting from the action of
pyrethroids on the sodium and chloride channels.
p.105
3.5.3 Animal-to-Human Extrapolations
Limited information
is available regarding the specific mechanisms involved in the toxicokinetics
of
pyrethroids in
either humans or animals. Therefore, it
is difficult to assess how the toxicokinetic data
obtained from
studies in laboratory animals may differ from that obtained in humans. It is presumed that the toxicokinetic mechanisms involved are generally
similar in all mammalian species, although quantitative interspecies
differences most certainly exist. Absorption
and distribution of pyrethroids appear to be largely determined by the
lipid-soluble nature of these compounds. Therefore, it is expected that the absorption
and distribution of pyrethroids in humans will be similar to that observed in
other mammalian species. In both humans
and animals, pyrethroids appear to be metabolized by nonspecific microsomal
carboxyesterases and microsomal mixed function oxidases, which are located in
nearly all tissue types and are common to all mammalian species. Since the metabolites that have been
identified in humans have also been identified in other mammalian species, it
is unlikely that there are significant qualitative differences between humans
and most animal species for the major metabolic pathways for pyrethroids
(Anadón et al. 1991b; Eadsforth and Baldwin 1983; Eadsforth et al. 1988;
Elliott et al. 1976; Gaughan et al. 1977; Leng et al. 1997b; Woollen et al.
1992). The cat appears to be an
exception, exhibiting increased sensitivity to the toxic actions of
pyrethroids. This increased sensitivity
may be the result of less efficient hepatic glucuronidation in the cat (Whittem
1995), a second step in the metabolism of pyrethroids in mammalian systems. Pyrethroids and their metabolites are excreted
primarily in the urine and feces, and it is likely that mechanisms involved are
the same in all mammalian species. If interspecies
differences exist in sodium channel kinetics, such differences could increase
the uncertainty related to interspecies extrapolation.
p.106
3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE
AXIS
Recently, attention
has focused on the potential hazardous effects of certain chemicals on the
endocrine
system because of
the ability of these chemicals to mimic or block endogenous hormones. Chemicals
with this type of
activity are most commonly referred to as endocrine disruptors. However, appropriate
terminology to
describe such effects remains controversial. The terminology endocrine disruptors,
initially used by
Colborn and Clement (1992), was also used in 1996 when Congress mandated the
Environmental
Protection Agency (EPA) to develop a screening program for “...certain
substances
[which] may have an
effect produced by a naturally occurring estrogen, or other such endocrine
effect[s]...”. To meet this mandate, EPA convened a panel called
the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC),
which in 1998 completed its deliberations and made
recommendations to
EPA concerning endocrine disruptors. In
1999, the National Academy of Sciences released a report that referred to these
same types of chemicals as hormonally active agents. The terminology endocrine modulators has
also been used to convey the fact that effects caused by such chemicals may not
necessarily be adverse.
Many
scientists agree that chemicals with the ability to disrupt or modulate the
endocrine system are a potential threat to the health of humans, aquatic
animals, and wildlife. However, others think that
endocrine-active chemicals do not pose a significant health risk, particularly
in view of the fact that hormone mimics exist in the natural environment.
p.106-107
Examples of natural
hormone mimics are the isoflavinoid phytoestrogens (Adlercreutz 1995;
Livingston 1978; Mayr et al. 1992). These
chemicals are derived from plants and are similar in structure and action to
endogenous estrogen. Although the public
health significance and descriptive terminology of substances capable of affecting
the endocrine system remains controversial, scientists agree that these
chemicals may affect the synthesis, secretion, transport, binding, action, or
elimination of natural hormones in the body responsible for maintaining
homeostasis, reproduction, development, and/or behavior (EPA 1997). Stated differently, such compounds may cause
toxicities that are mediated through the neuroendocrine axis. As a result, these chemicals may play a role
in altering, for example, metabolic, sexual, immune, and neurobehavioral function.
Such chemicals are also thought to be
involved in inducing breast, testicular, and prostate cancers, as well as
endometriosis (Berger 1994; Giwercman et al. 1993; Hoel et al. 1992). The potential for pyrethroids to act as
endocrine disruptors has been investigated in a limited number of studies in
vitro (Eil and Nisula 1990; Garey and Wolff 1998; Go et al. 1999). Using Ishikawa Var-I human endometrial cancer
cell line and the T47D human breast cancer cell line, cell lines that produce phosphatase
as an indicator of hormonal activity, Garey and Wolff (1998) demonstrated that
fenvalerate and phenothrin induced significant estrogenicity at concentrations
of 10 μM. Similar tests performed using
d-trans-allethrin and permethrin did not result in apparent estrogenicity. None of the four pyrethroids showed
significant estrogen antagonist activity or acted as progestin, but fenvalerate
and d-trans-allethrin significantly antagonized the action of progesterone in
T47D cells. Go et al. (1999) found that
micromolar concentrations of phenothrin or fenvalerate induced pS2 expression
in the MCF-7 human breast cell carcinoma cell line by 5-fold, indicating that
these pyrethroids may induce estrogenic activity. The fact that phenothrin-induced pS2
expression was suppressed by antiestrogen co-treatment is a further indication
that phenothrin may affect endocrine function. Other pyrethroids (fenvalerate, permethrin,
and cypermethrin) were also found to induce pS2 expression (Chen et al. 2002).
Several pyrethroids
have been shown to interact with androgen binding sites in dispersed intact
human genital skin fibroblasts, with varying degrees of potency, but at levels
comparable to those resulting in the same order of binding observed using
cimetidine, a known inhibitor of androgen receptor binding (Eil and Nisula
1990). Pyrethrins and bioallethrin were found
to displace [3H]testosterone from sex hormone binding globulin in human plasma,
at inhibitory levels up to 50% (Eil and Nisula 1990).
Data regarding
potential for pyrethrins and pyrethroids to act as endocrine disruptors in
vivo include
findings of reduced
reproductive organ weights, significantly altered sperm characteristics, and reduced plasma
testosterone levels in male rats administered oral doses of pyrethroids for up
to 65 days (Abd El-Aziz et al. 1994; Abd El-Khalek et al. 1999; Hassan et al.
1993). However, there was no evidence of
androgenicity or estrogenicity following repeated oral gavage exposure of
castrated male rats (5-day Hershberger assay) and ovariectomized female rats
(3-day uterotrophic assay) to esfenvalerate, fenvalerate, or permethrin at
doses high enough to elicit classical clinical signs of neurotoxicity (Kunimatsu
et al. 2002).
p.108
3.9
INTERACTIONS WITH OTHER CHEMICALS
Pyrethroids are
eliminated through biotransformation reactions that are catalyzed by microsomal
enzymes, although
the specific enzymes involved have not been identified. Results from studies of
laboratory animals
show that inhibition of hydrolytic reactions and of oxidative metabolism
increases the toxicity of pyrethroids, while induction of microsomal oxidases
decreases the toxicity of pyrethroids (Hutson 1979). Therefore, it appears that chemicals or drugs
capable of inducing or inhibiting the enzymes involved in
pyrethroid biotransformation reactions can alter the metabolism of pyrethroids. Since the metabolites
of pyrethroids are more water soluble than the parent compounds, they are less likely to cross the
blood-brain barrier and are more easily excreted by the kidney and liver than
the parent compounds. Thus, alterations
in the metabolism of pyrethroids through inhibition or induction of microsomal
enzymes could alter the distribution and excretion of pyrethroids. For example, piperonyl butoxide, a common
insecticide synergist, inhibits microsomal enzymes and potentiates the toxic
effects of pyrethrins and pyrethroids to mammals.
Limited evidence
exists to suggest that some Gulf War veterans with chronic, nonspecific
symptoms may
be experiencing
neurological dysfunction due to low-level exposures to mixtures of
anti-cholinesterase
agents, insect repellents,
and pyrethroids that might have additive or synergistic effects (Haley and Kurt
1997; Haley et al.
1997a, 1997b). To test this hypothesis,
McCain et al. (1997) administered rats oral
doses of a
short-acting anti-cholinesterase agent (pyridostigmine bromide), an insect
repellent (DEET),
and permethrin,
alone or in combination, and found that combined exposure resulted in a higher
degree of lethality than that which would be expected from additive lethal
values obtained for each chemical separately. Abu-Qare and Abou-Donia (2001a) demonstrated
that co-administration of DEET and
permethrin to the
skin of rats resulted in significantly increased release of brain mitochondrial
cytochrome c,
whereas no significant effect was seen following applications of either
chemical alone. The effects of combined exposure
may be the result of synergistic effects that are expressed following absorption
since results of an in situ assay of mouse skin revealed that DEET
appeared to inhibit the dermal absorption of permethrin (Baynes et al. 1997). Synergistic effects could potentially occur in workers who spray a
variety of pesticides, although no data were available to indicate such
effects. Another indication of an
adverse toxic interaction between pyrethroids and other chemicals is the
finding of significantly increased chromosomal aberrations in bone marrow cells
of rats orally administered repeated doses of cypermethrin and lead, in
combination (Nehéz et al. 2000). This
effect was significant when compared with both control animals and those
administered cypermethrin or lead separately, and appeared to be greater than
an additive effect.
p.114-115
Therefore, my & my son's original exposure
to the active ingredient Bifenthrin
in the termiticide Biflex (called “Talstar” in the U.S.) PLUS THE HYDROCARBON SOLVENT ADDITIVES IN THE PESTICIDE MIXTURE
cannot be ruled out as having synergist effects inside our bodies. This applies also to exposed CH residents in
McQuade Avenue and demonstrates that this pesticide technology is not proven
SAFE.
3.10 POPULATIONS THAT ARE
UNUSUALLY SUSCEPTIBLE
A susceptible population will exhibit a different or enhanced response
to pyrethrins or pyrethroids than
will most persons exposed to the same level of pyrethrins or pyrethroids
in the environment. Reasons
may include genetic makeup, age, health and nutritional status, and
exposure to other toxic substances
(e.g., cigarette smoke). These parameters result in reduced
detoxification or excretion of pyrethrins or
pyrethroids, or compromised function of organs affected by pyrethrins or
pyrethroids…
p.115
3.11.1
Reducing Peak Absorption Following Exposure
Inhalation Exposure. There is little information regarding the degree of absorption following
inhalation exposure
to pyrethrins or pyrethroids, although it is presumed that absorption will
occur via
diffusion across
lipid membranes. However, there is no known effective way
to reduce absorption
following inhalation exposure to pyrethrins or
pyrethroids.
p.116
3.12.1 Existing Information on Health Effects of
Pyrethrins and Pyrethroids
The existing data on
health effects of inhalation, oral, and dermal exposure of humans and animals
to
pyrethrins and
pyrethroids are summarized in Figure 3-5.
The purpose of this figure is to illustrate the existing information
concerning the health effects of pyrethrins and pyrethroids. Each dot in the figure indicates that one or
more studies provide information associated with that particular effect. The dot does not necessarily imply anything
about the quality of the study or studies, nor should missing information in
this figure be interpreted as a “data need”.
A data need, as defined in ATSDR’s Decision Guide for Identifying
Substance-Specific Data Needs Related to Toxicological Profiles (Agency for
Toxic Substances and Disease Registry 1989), is substance-specific information
necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more
broadly as any
substance-specific
information missing from the scientific literature.
Available
data regarding health effects in humans exposed to pyrethrins or pyrethroids
largely concern occupational exposure during crop applications in which
exposure was considered to have occurred primarily via dermal contact, although
inhalation exposure could not be ruled out. Therefore, Figure 3-5 indicates that information exists for both
inhalation and dermal exposure routes. A
number of human cases involved intentional ingestion of pyrethroids. Both inhalation and dermal exposures were
likely in the few reported cases of reactive airway responses. Some occupational exposures were considered to have been of
intermediate or chronic duration due to repeated exposures ranging from weeks
to years. However, observed health
effects following repeated exposure to pyrethrins or pyrethroids were similar
to those that characterize acute pyrethroid poisoning.
p.120
The database for
health effects following oral exposure to pyrethrins or pyrethroids in
experimental
animals is
substantial. However, as can be seen in
Figure 3-5, information regarding health effects
following inhalation
or dermal exposure is more limited. The
nervous system appears to be the
predominant target
of pyrethrin- and pyrethroid-induced toxicity. Genotoxicity data on pyrethrins and
pyrethroids are
available from studies in vivo and in vitro; results of
genotoxicity tests are predominantly
negative. Pyrethrum extract (containing 57.7%
pyrethrins) may induce cancer in laboratory animals as
evidenced by
increased incidences of liver and thyroid tumors in rats exposed orally for a
lifetime. Based on currently available
animal cancer bioassays, synthetic pyrethroids do not appear to pose a
particular carcinogenicity concern.
Figure 3-5. Existing
Information on Health Effects of Pyrethrins and Pyrethroids
3.12.2 Identification of Data Needs
Acute-Duration Exposure. Reports in which inhalation could be considered to be a significant route of exposure to pyrethrins or pyrethroids are mainly available from studies of workers involved in the manufacture or use of the chemicals (Chen et al. 1991; Flannigan and Tucker 1985; Flannigan et al.
1985b; He et al. 1988, 1989, 1991; Knox et al. 1984; Kolmodin-Hedman et al. 1982; LeQuesne and
Maxwell 1980; Moretto 1991; Shujie et al. 1988; Tucker and Flannigan 1983; Zhang et al. 1991).
Limitations associated with these reports include lack of quantitative exposure data, lack of data on
duration of exposure, and the possibility of multiple routes of exposure (i.e., dermal as well as inhalation). Dermal exposure was considered to have been the principal exposure route among individuals involved with spraying pyrethroids. A limited report in which inhalation exposure was considered to be the primary exposure route did not include exposure levels (Lessenger 1992). Limited animal inhalation toxicity data are available for pyrethrins and pyrethroids (Curry and Bennett 1985; Flucke and Thyssen 1980; Hext 1987; Kavlock et al. 1979; Miyamoto 1976; Pauluhn and Thyssen 1982; Schoenig 1995), but these studies mainly concerned lethality or used exposure levels at which serious neurological effects were elicited. Due to the limited nature of the human and animal data, an acute inhalation MRL could not be derived. Additional peer-reviewed animal studies designed to examine the effects of acute inhalation exposure to pyrethrins and pyrethroids would strengthen the database of currently available information.
The nervous system is the major target of pyrethrin- and pyrethroid-induced toxicity. Numerous reports describe clinical signs of neurotoxicity in humans (Gotoh et al. 1998; He et al. 1989; Peter et al. 1996) and laboratory animals (Eriksson and Nordberg 1990; Hudson et al. 1986; Parker et al. 1983, 1984a, 1984b, 1985; Ray and Cremer 1979; Southwood 1984) following acute oral exposure to relatively high doses of pyrethrins or pyrethroids. One research group (Eriksson and coworkers) has reported neurological effects in adult mice that had been administered acute oral doses of pyrethroids during critical stages of neonatal brain growth (postpartum days 10–16) at exposure levels much lower than those eliciting the classical clinical signs of neurotoxicity (Ahlbom et al. 1994; Eriksson and Fredriksson 1991; Eriksson and Nordberg 1990; Talts et al. 1998a). Another group of investigators (Ray et al. 2002) duplicated the study design of Eriksson and coworkers, but did not observe a toxicologically significant neurological effect. Additional studies designed to assess developmental neurotoxic effects at relatively low levels of oral exposure to pyrethrins and pyrethroids could serve to support or refute the findings of Eriksson and coworkers.
Paresthesia (an abnormal cutaneous sensation sometimes described as tingling, burning, stinging, numbness, and itching) has been widely reported by individuals occupationally exposed to pyrethroids (Flannigan and Tucker 1985; Flannigan et al. 1985b; Knox et al. 1984; LeQuesne and Maxwell 1980; Tucker and Flannigan 1983). Higher levels of exposure to various pyrethroids have resulted in mild acute pyrethroid poisoning that included dizziness, headache, and nausea (Chen et al. 1991; Moretto 1991; Shujie et al. 1988; Zhang et al. 1991). However, human studies typically involved the potential for multiple exposure routes and exposure levels were not quantified. Limited available peer-reviewed animal data indicate neurotoxicity following acute dermal exposure to pyrethroids (El-Elaimy 1986; Meyer 1999; Mitchell et al. 1988). Analysis of results of acute dermal toxicity testing by the pesticide industry might preclude the need for additional animal studies.
Acute-duration inhalation MRLs were not derived for pyrethrins or pyrethroids due to the limited
available information concerning health effects following inhalation exposure to pyrethrins or
pyrethroids. Acute-duration oral MRLs were derived for permethrin, cypermethrin, and cyhalothrin. As
information becomes available for additional pyrethroids, acute-duration oral MRLs can be derived for
them as well.
p.120-122
Intermediate-Duration Exposure. Available reports of toxicoses in humans occupationally
exposed to pyrethrins or pyrethroids include multiple exposure routes (dermal, inhalation, and possibly
oral) and lack quantitative exposure data. Oral data and limited inhalation data were available for
laboratory animals repeatedly exposed to pyrethrins or pyrethroids (Cabral and Galendo 1990; DOD
1977; Flucke and Schilde 1980; Hext et al. 1986; IRIS 2003a, 2003b, 2003c; Ishmael and Litchfield 1988;
Miyamoto 1976; Mohan et al. 1998; Parker et al. 1984a, 1984b; Schoenig 1995), but there were few
indications that repeated or continuous exposure result in cumulative neurological effects in animals
exposed as adults. Intermediate-duration inhalation MRLs were not derived for pyrethrins or pyrethroids due to the limited available information concerning health effects following inhalation exposure to pyrethrins or pyrethroids. Intermediate-duration oral MRLs were derived for permethrin and cyhalothrin. As information becomes available for additional pyrethroids, intermediate-duration oral MRLs can be derived for them as well.
Chronic-Duration Exposure and Cancer. Available reports of toxicity in humans occupationally
exposed to pyrethrins or pyrethroids include multiple exposure routes (dermal, inhalation, and possibly
oral) and lack quantitative exposure data. Oral data were available for laboratory animals chronically
exposed to pyrethrins or pyrethroids (Cabral and Galendo 1990; Hext et al. 1986; IRIS 2003a, 2003b,
2003c; Ishmael and Litchfield 1988; Parker et al. 1984a; Schoenig 1995), but there were no indications
that repeated or continuous exposure might result in cumulative neurological effects. Chronic-duration
inhalation MRLs were not derived for pyrethrins or pyrethroids due to the limited available information
concerning health effects following inhalation exposure to pyrethrins or pyrethroids. Chronic-duration
oral MRLs were not derived for pyrethrins or pyrethroids, due to inadequate data. Available cancer bioassays of animals administered pyrethrins or selected pyrethroids orally provide equivocal evidence of a carcinogenic effect (Cabral and Galendo 1990; EPA 1994c; Ishmael and Litchfield 1988; Miyamoto 1976; Parker et al. 1983, 1984a; Schoenig 1995). Additional information from the pesticide industry should be reviewed in the process of assessing the need for additional studies.
Genotoxicity. No information was located regarding the genotoxicity of pyrethrins or pyrethroids in
humans. Limited
information indicated that pyrethrins were not mutagenic in bacterial test
systems in vitro (see Table 3-3). Type I and Type II pyrethroids
generally tested negative for mutagenicity in prokaryotic test systems, but some
positive results were obtained for mutation in yeast cells exposed to selected
Type I and Type II pyrethroids (see Tables 3-6 and 3-7). Tests in mammalian systems, both in vivo and
in vitro, indicated that Type I and Type II pyrethroids had the potential
to induce chromosomal
damage (see Tables 3-6 and 3-7).
Reproductive Toxicity. No information was located regarding pyrethrin- or pyrethroid-induced
reproductive toxicity in humans. Reproductive toxicity was not observed in rats administered oral doses
of pyrethrins in the diet at concentrations resulting
in average daily doses of 240 mg/kg for 2 generations (Schoenig 1995). One 3-generation study found no evidence for
reproductive toxicity from fenpropathrin at an oral dose level of 25 mg/kg/day
(Hend et al. 1979). However, Abd
El-Aziz et al. (1994) reported significantly reduced fertility in male rats
following intermediate-duration oral exposure to deltamethrin at a dose level
of 1 mg/kg/day. Additional reproductive
toxicity studies could be designed to support or refute these results.
Developmental Toxicity. No information was located regarding pyrethrin- or pyrethroid-induced
developmental toxicity in humans. Most available developmental toxicity studies in animals do not
indicate that pyrethrins or pyrethroids might be considered to be developmental toxicity hazards. The
World Health Organization (WHO 2001), and EPA (IRIS 2003f) reviewed a number of unpublished or
proprietary developmental toxicity studies performed for various chemical organizations. The summaries of WHO (2001) and EPA (IRIS 2003f) indicate that classical developmental effects are not elicited following exposure to pyrethroids.
p.123
Please
take note of this Internet information:
A New Way to
Inherit Environmental Harm [http://www.rachel.org/bulletin/index.cfm?issue_ID=2501] June 9, 2005 by Tim Montague:
"New research shows that the environment is more important to health than
anyone had imagined. Recent information indicates that toxic effects on
health can be inherited by children and grandchildren, even
when there are no genetic mutations involved. These inherited
changes are caused by subtle chemical influences, and this new field of
scientific inquiry is called "epigenetics."...
(http://www.womenandlife.org/WLOE-en/information/ecology/health/healthmenu.html).
Recent studies by Eriksson and
coworkers suggest that exposure to pyrethroids during neonatal stages of development
when the brain is rapidly growing, may result in adverse neurological effects
(changes in MACh receptor density in the cerebral cortex and increased
spontaneous locomotor behavior) that are not apparent until adulthood (Ahlbom
et al. 1994; Eriksson and Fredriksson 1991; Eriksson and Nordberg
1990; Talts et al. 1998a). However, limitations in study design and lack of success in duplicating the
results (Ray et al. 2002; Tsuji et al. 2002) render the studies of Eriksson and coworkers of questionable value for the purpose of risk assessment. Additional studies should be designed to support or refute the findings of Eriksson and coworkers.
Immunotoxicity. A few cases of hypersensitive responses in humans exposed to pyrethrins and pyrethroids have been documented in available literature (Box and Lee 1996; Carlson and Villaveces 1977; Wagner 2000; Wax and Hoffman 1994). Available information regarding immunotoxicity in animals was limited to oral studies in which administration of selected pyrethroids resulted in immunotoxic effects such as suppression of the humoral immune response, alterations in lymphocytes, leukopenia, altered natural killer cell activity, and decreased spleen weight (Blaylock et al. 1995; Demian 1998; Demian and El-Sayed 1993; Dési et al. 1986; Lukowicz-Ratajczak and Krechniak 1992; Varshneya et al. 1992). No adequate studies are available in humans to assess the immunotoxic potential of pyrethrins or pyrethroids. Studies measuring specific immunologic parameters in occupationally exposed populations might provide useful information. However, inherent variation among human subjects would necessitate very large sample sizes. Animal studies designed to investigate the mechanism for pyrethroid induced immunotoxicity might help to identify special populations at risk for such effects.
Neurotoxicity. Abundant human data show that exposure to large amounts of pyrethroids, either by accidental or intentional ingestion or by dermal and inhalation exposure during unprotected handling or spraying of pyrethroids, may result in clinical signs of neurotoxicity (Chen et al. 1991; Flannigan and Tucker 1985; Flannigan et al. 1985b; Gotoh et al. 1998; He et al. 1989, 1991; Knox et al. 1984; LeQuesne and Maxwell 1980; Moretto 1991; Peter et al. 1996; Shujie et al. 1988; Tucker and Flannigan 1983; Zhang et al. 1991). Exposure of laboratory rodents to selected Type I and Type II pyrethroids has been shown to trigger typical signs of Type I (aggressive behavior and increased sensitivity to external stimuli, fine tremor, prostration with coarse whole body tremor, elevated body temperature, and coma) and Type II (pawing and burrowing behavior, profuse salivation, increased startle response, abnormal hindlimb movements, and choreoathetosis) pyrethroid poisoning. Although the majority of animal studies reporting neurotoxic effects employed oral exposure (EPA 1988c, 1991a, 1991b, 1992b, 1992c, 1994b; Eriksson and Nordberg 1990; Hudson et al. 1986; McDaniel and Moser 1993; Parker et al. 1983, 1984a, 1984b, 1985; Ray and Cremer 1979; Southwood 1984), these effects were also elicited following inhalation and dermal exposure (Curry and Bennett 1985; El-Elaimy 1986; Pauluhn and Thyssen 1982; Schoenig 1995). Several investigators reported typical signs of Type I or Type II pyrethroid poisoning in laboratory rodents during repeated oral administration of pyrethrins or pyrethroids (from 2 days to 2 years), but there were few indications that repeated or continuous exposure might result in cumulative neurological effects (Cabral and Galendo 1990; DOD 1977; Flucke and Schilde 1980; Hext et al. 1986; IRIS 2003a, 2003b, 2003c; Ishmael and Litchfield 1988; Mohan et al. 1998; Parker et al. 1984a, 1984b; Schoenig 1995).
Some investigators have reported
signs of neurotoxicity such as altered locomotor activity, altered acoustic
startle response, decreased active avoidance response, and changes in brain neurotransmitter
concentrations at pyrethroid exposure levels below those eliciting clinical
signs of Type I or Type II pyrethroid poisoning (Crofton and Reiter 1988;
Hijzen et al. 1988; Husain et al. 1991; Mandhane and Chopde 1997; Mitchell et
al. 1988; Moniz et al. 1994; Spinosa et al. 1999). Additional studies of the neurotoxicity of
pyrethrins and pyrethroids should assess sensory function in humans and sensitivity
of unique populations such as farm workers, children of farm workers, the
elderly, and veterans of the Gulf War.
p.123-125
Epidemiological and Human Dosimetry Studies. Available information regarding the health
effects of pyrethrins and pyrethroids in humans mainly concerns reports of neurological effects following accidental or intentional ingestion or during unprotected handling or spraying (Chen et al. 1991; Flannigan and Tucker 1985; Flannigan et al. 1985b; Gotoh et al. 1998; He et al. 1989, 1991; Knox et al. 1984; LeQuesne and Maxwell 1980; Moretto 1991; Peter et al. 1996; Shujie et al. 1988; Tucker and Flannigan 1983; Zhang et al. 1991). Occupational exposure to pyrethrins and pyrethroids may be confounded by differences in specific formulations and by concurrent exposures to other pesticides. Pesticide applicators, farm workers, individuals involved in production of pyrethrins or pyrethroids, and individuals exposed in recently sprayed homes or offices might serve as a focus for well-designed epidemiological studies for further assessment of neurological effects of pyrethrins and pyrethroids, as well as assessment of other potential adverse effects, such as immunotoxicity. Studies of dosimetry would be useful in future epidemiological studies.
6. POTENTIAL
FOR HUMAN EXPOSURE
6.1 OVERVIEW
Technical-grade (concentrated) pyrethrins and pyrethroids are usually
formulated (mixed with carriers
and solvents) for use in commercial products, and the toxicity of the
formulated commercial product is
not necessarily identical to the toxicity of the pure material. Inert ingredients and contaminants in
pyrethroid formulations often contain suspected carcinogens or chemicals
that depress the central nervous
system (Mueller-Beilschmidt
1990).
p.168
Pyrethrins and pyrethroids are extremely toxic to fish and
environmentally beneficial insects such as bees. In field situations, the
hazard to bees is often lessened because bees are repelled by pyrethroids,
which reduces their contact with plant surfaces that have recently been sprayed
and decreases the chance of receiving a lethal dose. The natural pyrethrins and several pyrethroids
are relatively nontoxic to mammals, but some pyrethroids such as deltamethrin,
flucythrinate, cyhalothrin, permethrin, and tefluthrin have demonstrated
considerable toxicity (Metcalf 1995). For
example, flea applications containing a high concentration of permethrin made
for use on dogs have often been associated with the accidental poisoning of
cats when improperly used.
p.169
6.6 EXPOSURES
OF CHILDREN
This section focuses on exposures
from conception to maturity at 18 years in humans. Differences from
adults in susceptibility to
hazardous substances are discussed in 3.7 Children’s Susceptibility.
Children are not small adults. A
child’s exposure may differ from an adult’s exposure in many ways.
Children drink more fluids, eat more food, breathe more air per kilogram
of body weight, and have a
larger skin surface in proportion to their body volume. A child’s diet often differs from that of
adults.
The developing human’s source of nutrition changes with age: from
placental nourishment to breast milk
or formula to the diet of older children who eat more of certain types
of foods than adults. A child’s
behavior and lifestyle also influence exposure. Children crawl on the floor, put things in
their mouths,
sometimes eat inappropriate things (such as dirt or paint chips), and
spend more time outdoors. Children
also are closer to the ground, and they do not use the judgment of
adults to avoid hazards (NRC 1993).
Children are exposed to
pyrethrins and pyrethroids by similar routes that affect adults. Ingestion of foods
is the most important exposure
pathway for children. The AVDI of
permethrin has been reported as
46.5 ng/kg-body weight/day for
6–11-month-old infants and 70.7 ng/kg-body weight/day for 2-year-old
toddlers (Gunderson 1995b). No measurements have been made of these
compounds in amniotic fluid,
meconium, cord blood, neonatal
blood, or any other tissues that may indicate prenatal exposure. No data
have been reported on the levels
of pyrethrins or pyrethroids in breast milk.
The tendency of young children to
ingest soil, either intentionally through pica or unintentionally through
hand-to-mouth activity, is well
documented. These behavioral traits can
result in ingestion of pyrethrins
and pyrethroids present in soil
and dust. Since these compounds are
adsorbed strongly to soils, they may
not be in a highly bioavailable
form. Young children often play on the
ground or on carpets and this will
increase the likelihood of dermal
exposure and inhalation of contaminated particles from soil, household
dust and treated surfaces. The
transfer of allethrin residues from a carpeted floor to human subjects
wearing dosimeter clothing was
studied (Ross et al. 1990). For gloves,
socks, shirts, and tights of
subjects performing standardized
aerobic exercises, the transfer coefficient ranged from 2.8 to 34.3 μg
allethrin/cm2 clothing for a
period of up to 12.5 hours after applying allethrin (via foggers) to the
carpet.
The transfer rates decreased with
time after application (Ross et al. 1990). Pyrethrins and pyrethroids are
also frequently used in products such
as pet shampoos or sprays, and since children often spend a great
deal of time playing with pets,
this can increase childhood exposure. Pyrethrins
and certain pyrethroids
have been employed in head lice
treatment products, which are often used on children.
p.197-198
7.2 ENVIRONMENTAL SAMPLES
In the analysis of
pyrethrins, the total residues of the six active compounds are often analyzed
for, but in
the analysis of
pyrethroids, the individual compounds are usually quantified (Chen and Wang
1996). An
extensive review of
the chromatographic methods employed for the determination of pyrethrins and
pyrethroids in
foods, crops, and environmental media has been published (Chen and Wang
1996). Many
pyrethroids such as bifenthrin,
cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, and
permethrin possess
one or more halogenated atoms which are sensitive to ECD. Often, derivitization is
used to create a
sensitive group for pyrethroids that do not possess halogenated atoms
(allethrin,
resmethrin,
phenothrin, and tetramethrin, for example), or to improve the sensitivity and
peak tailing
situations in some
halogenated pyrethroids (Chen and Wang 1996).
Consequently, GC/ECD is the most
popular analytical
approach for analyzing pyrethroids in environmental samples.
TOXICOLOGICAL PROFILE FOR PYRETHRINS AND PYRETHROIDS, September 2003, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public
Health Service, Agency for Toxic Substances and Disease Registry.
(UPDATE STATEMENT:
A Toxicological Profile for pyrethrins and pyrethroids, Draft for Public
Comment was released in September, 2001.
This edition supersedes any previously released draft or final
profile. Toxicological profiles are
revised and republished as necessary, but no less than once every three
years. For information regarding the
update status of previously released profiles, contact ATSDR at:
Agency for Toxic Substances and Disease Registry
Division of Toxicology/Toxicology Information
Branch
1600 Clifton Road NE,
Mailstop E-29
Atlanta, Georgia 30333)