Toxicologic Information About Insecticides
Used for Eradicating Mosquitoes
(West Nile Virus Control)
April 2005
Malathion is an organophosphate insecticide used extensively in agricultural and horticultural applications. It also is used in regional pest eradication programs to control boll weevil, medfly, and mosquitoes (ATSDR 2001). The use of malathion by ground application and aerial spraying is generally the preferred method of eradicating adult mosquitoes associated with West Nile Virus because of its relatively low toxicity to humans, other mammals, and birds compared with other organophosphate insecticides (EPA 2000a,b). Because malathion is toxic to aquatic organisms, direct application to bodies of water is generally avoided.
Section 1. Environmental Factors
Malathion degrades rapidly in the environment (ATSDR 2001). Malathion in the open environment undergoes hydrolysis, biodegradation, and photolysis roughly in that order of importance. The rate of transformation depends heavily on pH and organic content of the environmental medium.
Hydrolysis is not significant in water at pH 5. At pH 7, malathion may completely hydrolyze in 6–7 days, whereas at pH 9, hydrolysis is complete in less than 12 hours (EPA 2000a; ATSDR 2001). Under least-favorable conditions (i.e., low pH and little organic content), malathion can persist with a half-life of months or even years. However, under most conditions typically encountered in the environment, the half-life for hydrolysis in water appears to be roughly 7–14 days (ATSDR 2001).
In soil, malathion is expected to be highly mobile, but it should not volatilize significantly. Biodegradation in soil is rapid, with 80%–95% biodegradation occurring in 10 days; it may be much faster, depending on soil content. Its half-life in soil is estimated by various authors from <1 day to 6 days, depending on the pH and the degradation pathway studied (ATSDR 2001).
If released to air, malathion should exist solely as a vapor in the ambient atmosphere and be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals; the estimated half-life for this reaction in air is ~5 hours. Malathion may also undergo photolysis (ATSDR 2001).
Section 2. Potential for Exposure
The general population is not likely to be exposed to large amounts of malathion. However, some exposure to residues of malathion is possible; as many studies show, malathion has been detected in foods and atmosphere samples. Populations living within or near areas of heavy malathion use are at increased risk for exposure to relatively larger amounts of malathion through dermal contact with contaminated plants, by inhalation of the mist formed from the applied insecticide, or by ingestion of water or foodborne residues. Dermal contact appears to be the major route of exposure. Ingestion also can be an important route, but inhalation has not been shown to be a significant route of exposure to malathion (ATSDR 2001).
Section 3. Health Effects/Toxicity
The data reviewed by ATSDR for this summary strongly support the hypothesis that health effects from malathion actually result either from the oxygen analogue, malaoxon (CAS # 1634-78- 2;C10H12O7PS), or phosphorus thionate impurities. Malaoxon is both a metabolite and an environmental degradation by-product. The phosphorus thionates are impurities, environmental degradation by-products, and possibly precursors for production. This hypothesis is being investigated under the authorities of the Federal Insecticide, Fungicide, and Rodenticide Act. In the interim, the chemical similarities of malathion to malaoxon and the thionates justify the use of malathion as a surrogate for these potentially more toxic metabolites and degradation products (EPA 2000a).
Health Effect in Humans Exposed to Malathion
The principal toxicologic effect of malathion and other
organophosphate insecticides is cholinesterase inhibition.
Information about health effects in humans exposed to
organophosphate insecticides comes from case reports, case studies,
statistical surveys, and epidemiologic studies. Many of the case
reports cover people who have ingested malathion unintentionally or
have attempted suicide by ingestion. Other case reports involve
private residents who have applied malathion formulations improperly
to their lawns and gardens or were exposed through inadequate
packaging or spillage. In many cases, only minor symptoms developed,
and were related more to the noxious odor than to the cholinergic
effects. Most epidemiologic studies involve workers who were engaged
in manufacturing, formulating, or applying malathion. A few surveys
of populations in areas where malathion has been used to control
mosquitoes or fruit flies also are available. Many of these studies
have been reviewed by Blondell (1998) and generally are limited by
such factors as inadequate documentation of exposure levels and
reporting biases.
- Common early signs or mild symptoms of acute cholinergic poisoning include miosis (pinpoint pupils), headache, nausea/vomiting, dizziness, muscle weakness, drowsiness, lethargy, agitation, and anxiety.
- Moderate or severe poisoning can result in chest tightness, difficulty breathing, bradycardia, tachycardia, hypertension, pallor, abdominal pain, incontinence, diarrhea, anorexia, tremor/ataxia, fasciculation, lacrimation, heavy salivation, profuse sweating, blurred vision, poor concentration, confusion, and memory loss.
- Life-threatening or very severe signs and symptoms, such as coma, seizures, respiratory arrest, pulmonary edema, loss of reflexes, and flaccid paralysis, can occur at high doses, such as in the cases of attempted suicide.
Malathion also may be slightly irritating to the skin and eyes. In addition to acute poisoning, chronic effects such as peripheral neuropathy, neurobehavioral effects, and the development of allergic sensitivity have been reported, but these effects are not well documented (Blondell 1998).
Experimental Studies in Humans
Laboratory studies conducted by Milby and Epstein (1964) in 87
volunteers showed that a single exposure to 10% malathion (95% pure)
induced contact sensitization in almost half the participants and
that 0.1 and 0.01% concentrations of 99.3% malathion evoked positive
responses in previously sensitized participants.
Moeller and Rider (1962) conducted a controlled study in which male volunteers were administered daily capsules containing malathion (purity not reported) in corn oil that provided an approximate dosage of 0.11 mg malathion/kg/day for 32 days, 0.23 mg malathion/kg/day for 47 days, or 0.34 mg malathion/kg/day for 56 days. Plasma and erythrocyte cholinesterase was determined twice weekly before, during, and after administration of malathion. Administration of 0.11 mg malathion/kg/day for 32 days or 0.23 mg/kg/day for 47 days did not produce any significant depression of plasma or erythrocyte cholinesterase activity, nor did it induce clinical signs. In phase three, 0.34 mg malathion/kg/day for 56 days caused a maximum depression of 25% in plasma cholinesterase approximately 3 weeks after cessation of treatment. A similar depression in erythrocyte cholinesterase was observed, but it occurred later. Routine blood counts conducted at the end of each study period did not detect any significant changes. No remarkable alterations in urinalyses were observed.
Male volunteers were exposed by inhalation to aerosol bombs that contained 0%, 5%, or 20% of malathion for 2 hours/day for 42 days (Golz 1959). Exposure concentrations were calculated as 0, 5.3, 21, and 85 mg/m3 by adjusting the application rate. These exposures did not result in changes in erythrocyte or plasma cholinesterase activity. The only effects noted were nasal and eye irritation at the highest concentration.
Health Effects Possibly Related to Municipal Use of Malathion
for Mosquito Control
The Florida Department of Health attempted to evaluate adverse
health effects potentially related to spraying to control the
Mediterranean fruit fly outbreak of 1998 (CDC 1999). The estimated
crude rate of malathion-related illnesses associated with the
eradication effort was calculated at nine cases per 10,000 residents
in the exposed areas. Of 230 reports of illness received, 34 (15%)
were classified as probable, and 89 (39%) were classified as
possible. Among these 123 cases, the acute signs and symptoms
reported were respiratory (71%), gastrointestinal (63%), neurologic
(60%), dermal (23%), and ocular (19%).
The report highlighted four cases in humans, two of whom were exposed after spraying:
- One person exposed while removing a pool cover with malathion residue.
- One person was exposed by direct contact with pesticide residue on fresh grass trimmings.
- One person worked outside on his roof during aerial spraying.
- One person suffered an acute exacerbation of a chronic asthmatic condition.
The California Department of Health Services conducted indirect assessments and symptom prevalence surveys to determine whether aerial application of malathion bait used to eradicate the Mediterranean fruit fly in Santa Clara County, California, posed a health hazard to the public (Kahn et al. 1992). In one indirect assessment, the records of a major hospital emergency department were compared during the first 5 weeks of spraying, the 2 weeks before spraying, and a corresponding 7- week period the year before. The number of visits did not differ significantly, and none of the hospital emergency departments in the county reported cases of pesticide poisoning. Another assessment of the frequency of ambulance calls in the same periods also showed no significant differences, but this assessment was relatively insensitive. An assessment for an increase in cases of asthma at a medical school hospital showed no increase, but the number of cases in this study were too small for definitive conclusions. In the symptom prevalence surveys—one an on-site home visit study, the other a telephone survey—no evidence was found that indicated the aerial spraying of malathion caused any detectable increase in symptoms.
Studies to determine whether an increase in fetal loss, low birthweight, and birth defects occurred in the same malathion program in Santa Clara County, California, were negative (Grether et al. 1987; Thomas et al. 1992). However, a statistically significant association between the incidence of gastrointestinal anomalies in offspring and exposure to malathion during the second trimester of pregnancy and a moderate association between stillbirths was reported by Thomas et al. (1992). When offspring of fathers exposed to malathion were examined, no increase in congenital malformations were found (Garcia et al. 1998).
Cases of possible immediate and delayed hypersensitivity reactions to malathion or to a corn syrup bait were investigated among 10 people who had developed dermatitis within a week of exposure to aerial application of malathion in Southern California (Schanker et al. 1992). The authors found one case of possible immediate IgE reaction to malathion bait and another case of irritant reaction to malathion and to the bait but no cases of delayed type hypersensitivity. Schanker et al. (1992) noted that, because of the low participation rate in the study, no specific conclusions could be drawn regarding the rate of sensitivity in the population.
Health Effects in Laboratory Animals
Studies in laboratory animals exposed to malathion dermally,
orally, or by inhalation are summarized in Table 1, with
no-observed-adverse-effect levels (NOAELs) and
lowest-observed–adverse-effect levels (LOAELs) indicated.
At very high doses, malathion exposure can lead to death. Acute dermal and ocular exposure can cause slight irritation. Otherwise, most of the studies indicate that similar cholinergic effects, along with serious decreases in the plasma, erythrocyte, and brain cholinesterase, occur regardless of route of exposure or duration, depending on the dose. Inhibition of cholinesterase, however, did not necessarily result in overt signs of cholinergic toxicity. The levels of cholinesterase generally return to preexposure levels after exposure ceases. Therefore, decreased levels of the cholinesterases do not necessarily result in nervous system effects. One study in hens indicated that exposure to malathion was not associated with delayed neurotoxicity.
Other effects observed in laboratory animals that have been exposed to malathion for acute, intermediate, or chronic durations included evidence of liver or kidney toxicity, hematologic effects, and immunologic effects. Other effects after inhalation exposure to malathion included irritation and mild lesions in the nasal cavity, larynx. and lungs.
Fetal anomalies were found when pregnant rats or pregnant rabbits were given oral doses of malathion by gavage, although increased mean resorption sites were found in rabbits and fetal deaths were found in rats at maternally toxic doses. No effects on reproductive ability of male or female rats were found when they were given food containing malathion before, during, and after mating for two generations. However, parental body weight decreased during gestation and lactation, and pup body weights decreased in the F1 and F2 pups during late lactation. In addition, malathion produces reversible damage to spermatogenic tissue of male rats and minor histopathologic lesions in testes, ovaries, and uterus of rats.
Carcinogenicity
The International Agency for Research on Cancer (IARC) classifies
malathion as Group 3, i.e., Anot classifiable as to its
carcinogenicity to humans@ (IARC 1983, 2001), because of lack of
evidence of carcinogenicity in experimental animals and lack of
human data. In two recent studies of animals exposed to malathion in
the diet, increased incidence of liver tumors was observed in male
and female mice (Slauter 1994) and female rats (Daly 1996a) only at
doses considered excessive (severe inhibition of cholinesterase
activity and marked decreased body weight).
In addition, in a study in which malaoxon, the cholinesterase-inhibiting metabolite of malathion, was administered to rats in their diet, equivocal evidence of carcinogenicity was reported on the basis of increased incidence of thyroid C-cell neoplasms in both male and female rats (NCI 1979a, Huff et al. 1985). However, EPA concluded that this study was inadequate to provide a definitive determination of the carcinogenicity of malaoxon in the rats because of limitations of the study. In a recent study of rats exposed to malaoxon in the diet, mononuclear cell leukemia was observed in the male rats (Daly 1996b). However, the findings in this study are not considered treatment-related because statistical significance occurred only in males at a dose determined to be excessive (increased death rates and severe cholinesterase activity) because no dose-response resulted and because incidences were within the historical control range (EPA 2000c).
On the basis of these and earlier studies on malathion that provided inconclusive evidence of carcinogenicity (because of deficiencies in study design, evaluation, and reporting) (IARC 1983, NCI 1978, 1979b), EPA has classified malathion as indicating Asuggestive evidence of carcinogenicity but not sufficient to assess human carcinogenic potential.@ Specifically, the EPA evaluation is based on (1) liver tumors in rats and mice only at excessive doses of malathion; (2) a few rare tumors—oral palate mucosa in female rats and nasal respiratory epithelium in male and female rats exposed to malathion; however, these tumors cannot be determined as either treatment-related or the results of random occurrence; and (3) malaoxon is not carcinogenic in male or female rats (EPA 2000c).
Genotoxicity
Genetic toxicology studies indicate that malathion did not cause
gene mutations in bacteria (Traul 1987) or unscheduled DNA synthesis
in cultured rat hepatocytes (Pant 1989). Also, malathion was neither
clastogenic nor aneugenic up to doses that showed clear cytotoxicity
for the target tissues in vivo (Gudi 1990). Although other studies
indicated that malathion was positive for chromosomal aberrations in
in vivo and in vitro studies (Flessel et al. 1993), the relevance of
these findings is not clear because the results were positive only
at cytotoxic doses or the types of induced aberrations were
asymmetric and therefore not consistent with cell survival. In
addition, the purity of the test substance was an issue (Yang 2000).
Results were weak but positive for sister chromatid exchange
induction at high, cytotoxic doses (Galloway et al. 1987). According
to EPA, the weight of evidence does not support a mutagenic hazard
or a role of mutagenicity in the carcinogenicity associated with
malathion (EPA 2000c).
Evaluation of data for malaoxon by EPA indicates that malaoxon is not mutagenic in bacteria but is a confirmed positive without S9 activation in the mouse lymphoma forward gene mutation assay (EPA 2000c). Malaoxon was not clastogenic in cultured Chinese hamster ovary cells. However, the findings from the mouse lymphoma assay suggest that malaoxon may induce both gene mutations and chromosome aberrations (Myhr and Caspary 1991). Nevertheless, malaoxon is not carcinogenic in rats (Yang 2000).
Table 1. Health Effect Levels of Malathion in Humans and
Laboratory Animals (PDF Version 98k)
Malathion appears to be readily absorbed after oral dosing and readily excreted, according to a study in orally dosed rats, where >90% of the dose was excreted (mostly in urine) within 72 hours, with most excretion in the first 24 hours (Reddy et al. 1989). Malathion does not appear to bioaccumulate in organs or tissues (HSDB 2002; Reddy et al. 1989). A dermal absorption study in humans determined that about 10% is absorbed dermally (Feldman and Maibach 1970). The major metabolites of malathion are malathion dicarboxylic acid and malathion monocarboxylic acid (Reddy et al. 1989). Although malaoxon is a minor metabolite, it is the active cholinesterase-inhibiting metabolite of malathion. Malathion’s mode of toxic action is the inhibition of cholinesterase, which is caused by malaoxon. The toxicity of malathion could be altered by interactions with chemicals that interfere with its detoxication, with chemicals that have the same mechanism of action, or with chemicals that induce hepatic microsomal enzymes.
Section 5. Standards and Guidelines for Protecting Human Health
Regulatory standards and guidance values are summarized in Table 2.
ATSDR has developed several minimal risk levels (MRLs) for malathion. An intermediate oral MRL of 0.02 mg/kg/day was derived on a NOAEL of 0.23 mg/kg/day for inhibition of plasma and erythrocyte cholinesterase activities in humans (Moeller and Rider 1962), using an uncertainty factor of 10 for the protection of sensitive humans populations. The LOAEL was 0.34 mg/kg/day. The chronic oral MRL of 0.02 mg/kg/day is based on a NOAEL of 2 mg/kg/day for inhibition of plasma and erythrocyte cholinesterase activities in male rats administered malathion in the diet for 2 years Daly (1996a) (Table 1), using an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for the protection of sensitive populations). The LOAEL was 29 mg/kg/day.
For inhalation exposure, an acute MRL of 0.2 mg/m3 was based on a NOAEL of 65 mg/m3 for inhibition of erythrocyte cholinesterase activity in rabbits (Weeks et al. 1977) (Table 1), using an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for the protection of sensitive populations). The LOAEL was 123 mg/m3. An intermediate inhalation MRL of 0.02 mg/m3 was based on a LOAEL of 100 mg/m3 for upper respiratory tract effects in rats (Beattie 1994) (Table 1). An uncertainty factor of 1,000 was applied (10 for animal to human extrapolation, 10 for the use of a LOAEL, and 10 for the protection of sensitive populations).
EPA (2000d) has proposed several risk assessment values in addition to the chronic oral reference dose (RfD) of 0.02 mg/kg/day based on the study by Daly (1996a). A proposed acute oral RfD of 0.5 mg/kg for 1-day exposure is based on a dose of 50 mg/kg/day, which resulted in decreased body weight in rabbits exposed on gestation days 6–18 in the study by Siglin (1985a). Although the 50- mg/kg/day dose was a LOAEL for decreased body weight during the 13 days of exposure, EPA considered this dose to be a NOAEL for decreased body weight for 1 day of exposure and applied an uncertainty factor of 100 (10 for interspecies extrapolation and 10 for human variability). EPA also proposed using an air concentration LOAEL of 100 mg/m3, 6 hours/day, 5 days/week, for 13 weeks in the study by Beattie (1994), converted to a dose of 25.8 mg/kg/day for short-, intermediate-, and long-term inhalation risk assessment. The uncertainty factor was 1,000 (10 for use of LOAEL, 10 for interspecies extrapolation, and 10 for human variability) to yield an inhalation risk assessment value of 0.03 mg/kg/day.
EPA also proposed a short- and intermediate-term dermal risk assessment value of 0.5 mg/kg/day on the basis of a NOAEL of 50 mg/kg/day for cholinesterase inhibition in rabbits exposed dermally for 6 hours/day, 5 days/week, for 3 weeks in the study by Moreno (1989).
Using these proposed values for the risk assessments for public health mosquito uses, EPA (2000d) concluded that the risk estimates for adults and toddlers for combined dermal and inhalation exposure did not exceed EPA’s levels of concern for residential bystander inhalation and dermal exposure from truck fogger and aerial ULV mosquito-control applications. This assessment included incidental oral ingestion for hand-to-mouth activities. Given the low levels of malathion used to control mosquito-borne diseases, ATSDR finds this assessment reasonable.
| Table 2. Regulatory Standards and Guidance Values for Malathion | ||
| Clean Water Act Maximum Contaminant Level(MCL)/Maximum Contaminant Level Goal(MCLG) | N/A | EPA 2002 |
| Safe Drinking Water Act: 1- and 10-day Health Advisories (Child) | 0.2 mg/L | EPA 2002 |
| Reference Dose (RfD) | 0.02 mg/kg/day* | EPA 2002 |
| Safe Drinking Water Act: Drinking Water Equivalent Level (DWEL) | 0.7 mg/L | EPA 2002 |
| Safe Drinking Water Act: Lifetime Health Advisory | 0.1 mg/L | EPA 2002 |
| Occupational Standards: Occupational Safety and Health Administration Permissible Exposure Limit (PEL) 8-hour timeweighted average | 15 mg/m³ (skin) | OSHA 2003 |
| National Institute for Occupational Safety and Health/Centers for Disease Control and Prevention (NIOSH/CDC) Recommended Exposure Limit (REL) | 10 mg/m³ (skin) | NIOSH 2003 |
| NIOSH/CDC Immediately Dangerous to Life or Health | 250 mg/m³ | NIOSH 2003 |
| ATSDR Oral Minimal Risk Level (MRL) Intermediate and Chronic | 0.02 mg/kg/day | ATSDR 2001 |
| ATSDR Inhalation MRL, Acute | 0.2 mg/m³ | ATSDR 2001 |
| ATSDR Inhalation MRL, Intermediate | 0.02 mg/m³ | ATSDR 2001 |
| Department of Transportation Reportable Quantity | 100 pounds | DOT 2002 |
| Environmental Protection Agency Reportable Quantity | 10 pounds | ATSDR 2001 |
| *EPA is reviewing the information in an application for reregistration of malathion and may shortly modify the RfD and establish an RfC. | ||
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