ENVIRONMENTAL RESEARCH 50, 256--261 (1989)

Congenital Anomalies Associated with Maternal Exposure to Oxydemeton-methyl

PABLO ROMERO, PAUL G. BARNETT, AND JOHN E . M I D T L I N G

Department of Family Medicine, Natividad Medical Center, Salinas, California 93912, and Department of Family and Community Medicine, University of California, San Francisco 94143

Received March 24, 1989

Thirty-five workers became ill after they entered a cauliflower field contaminated with residues of three different insecticides, the organophosphates oxydemeton-methyl (Meta- systox-R) and mevinphos (Phosdrin), and a carbamate, methomyl (Lannate). One crew member was pregnant with a 4-week-old fetus. At birth, the 3200-g female infant had mul- tiple cardiac defects, bilateral optic nerve colobomas, microphthalmia of the left eye, cere- bral and cerebellar atrophy, and facial anomalies. The cardiac defects included ventricular and atrial septal defects, stenosis of the pulmonary artery, and a patent ductus arteriosus. The child died at 14 days of age. There was no family history of birth defects, nor any maternal risk factor present, except that doxylamine (Bendectin) had been prescribed at 9 weeks fetal age. It is unlikely that doxylamine was responsible for the observed anomalies. Of the three chemicals involved, reproductive effects in test organisms have been observed only with oxydemeton-methyl. This case represents the first report of human malformations associated with prenatal exposure to this chemical. Further studies may be warranted t o determine if a causal relationship exists. © 1989 Academic Press, Inc.

INTRODUCTION

Pesticides pose an occupational hazard not only to those who work directly in producing, transporting, and applying them, but also to those who are accidentally exposed to pesticides drifting from the application site, or to chemical residues on crops and crop foliage. California physicians reported 875 occupational illnesses due to worker exposure to pesticide residues in 1985, and 238 occupational ill- nesses due to accidental exposure to pesticide applications (California Depart- ment of Food and Agriculture, 1986).

The acute affects of pesticide-induced illness are relatively well known. Little is known about the effects of these compounds on human reproduction. This article describes the multiple anomalies of an infant whose mother was exposed to in- secticides.

CASE REPORT

Thirty-five field workers entered a cauliflower field that had been sprayed 20 hr earlier with the organophosphate insecticides mevinphos (Phosdrin) and oxy- demeton-methyl (Metasystox-R) and the carbamate insecticide methomyl (Lan- nate). California regulations require that at least 72 hr elapse before workers return to the treated area.

After working for about an hour at their preharvest task of tying leaves over the head of the vegetable, the crew members reported a strong odor and complained of feeling ill. All 34 members of the crew and their foreman went to a local

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hospital, where they were decontaminated and examined. They presented with complaints of nausea, vomiting, headache, dizziness, burning nasal passages and eyes, blurred vision, and tremors. On examination, most subjects presented with cholinergic signs of excessive salivation and sweating, and two subjects were found to have constricted pupils. Blood samples were drawn, and red blood cell (RBC) cholinesterase was below the lower limit of the laboratory normal range in 33 of the 35 workers. Two workers received atropine, and 29 were hospitalized for 24 hr of observation.

One of the crew members was pregnant and subsequently gave birth to the infant who is the subject of this report. This 23-year-old woman complained of severe nausea, dizziness, lacrimation and salivation, shortness of breath, abdom- inal pains, headache, and visual disturbances on the day of her exposure to the insecticides. She was diagnosed clinically as suffering from poisoning by cholinesterase-inhibiting pesticides, but was not treated with atropine or pralidox- ime. Her RBC cholinesterase activity was 138 units, which was well below the lower limit of normal (normal range 210-360). Her plasma cholinesterase activity was 68 units (normal range 45-90).

Three weeks after her exposure, she presented with complaints of persistent headache, nausea, and vomiting. She had returned to work with the cauliflower tying crew, but discontinued work upon developing severe headache and nausea. A urine pregnancy test was positive. She reported that she had suspended use of her oral contraceptive just after her last menstrual period, which began 6 weeks prior to the day of exposure. This would place the fetal gestational age at approx- imately 4 weeks posffertilization at the time of exposure.

This gravida 5, para 4 woman had no known family history of birth defects, nor personal health history which constituted a risk factor other than pesticide expo- sure. Prior pregnancies had all been normal, and there was no paternal history of birth defects. The prenatal course was normal, except for continued complaints of nausea, occasional vomiting, dizzy spells accompanied by blurred vision, and lacrimation. Because of the severe nausea, doxylamine (Bendectin) was pre- scribed 11 weeks after the onset of the last menstrual period.

A 3200-g female infant was born by normal spontaneous vaginal delivery. The infant had a 1-min Apgar score of 6, and a 5-min Apgar of 8.

Physical examination of the infant revealed a loud systolic murmur, ocular hypertelorism with microphthalmia of the left eye, and bilateral optic nerve colobomas. Other abnormalities were noted including low set ears with dimin- ished lobes, a skin tag near the right ear, and the appearance of micrognathia. The child had cyanotic episodes, an abnormal cry, poor reflexes, and difficulty feed- ing. Shortly after birth, the infant became tachypneic and developed cardiac fail- ure. On echocardiogram, the infant was diagnosed as having an ostium primum atrial septa! defect, stenosis of the pulmonary valve with associated hypertrophied right ventricle, and a large patent ductus arteriosus, with a left to right shunt.

The infant was transferred for evaluation and management to the University of California, San Francisco. A C T scan showed diffuse cerebellar and cerebral atrophy, with the left side more involved than the right. A genetic consultation was obtained. The constellation of findings did not match any known syndrome.

258 ROMERO, BARNETT, AND MIDTLING

Chromosome studies were normal. Because the abnormalit ies were multiple and severe, it was decided that surgical intervention for the cardiac defects was not indicated. The infant expired at 14 days of age.

The pos tmor tem examinat ion revealed a patent ductus arteriosus 0.4 cm in diameter. The septum be tween the left and right a t r ium was primarily a mem- brane, with a round 0.8-cm-diameter opening. There was essentially a c o m m o n chamber formed by the left and right ventricles, with the ventr icular septal defect measuring 0.9 cm in length and up to 0.4 cm in width, opening above the tricuspid valve with a membranous septum down the center. The pulmonary valve was markedly stenosed, with the diameter of the opening 0.1 cm. The mitral valve was slightly deformed. Other than the previously described ophthalmologic findings, there were no other gross anomalies.

DISCUSSION

The rate at which the anomalies described in this case repor t occur is p r e s e n t e d in Table 1. Colobomas of the optic nerve are especially uncommon. This defect was found to occur at a rate of 0.588 in 10,000 births, during 1980-1985, by the Metropol i tan Atlanta Congenital Defects Program. None of the 69,146 births re- v iewed by the California program in 1983 had this defect.

The absence of either polydactyly or renal anomalies, and the presence of normal chromosomes , rule out syndromes such as t r isomy D. Since the infant was not transfused, there is no reason to suspect the accuracy of the ch romosome study.

In a repor t of four cases of optic nerve colobomas with serious defects in brain

TABLE 1 RATES OF CONGENITAL MALFORMATIONS PER 10,000 LIVE BIRTHS

ICD-9 Malformation code

California Birth

U.S. Metropolitan Defects Birth Atlanta Monitoring

Defects Congenital Program Monitoring Defects San Francisco

Program Program Bay area 1970-1980 1968-1979 1983

Patent ductus arteriosus 747.0 10.7 31.1 21.4 Ventricular septal defect 745.4 7.8 18.9 20.8 Atrial septal defect 745.5 1.5 8.0 19.2 Stenosis of the

pulmonary artery 747.3 NA" 3.7 2.6 Microphthalmus 743.1 0.5 2.5 2.5 Specific anomalies of the brain 742.4 NA 2.1 1.5

NA, not available. Note. Since each of these programs uses slightly different methods to identify and classify cases,

rates are not strictly comparable. Source. Birth Defects Monitoring Program, California Department of Health Services, Berkeley,

CA.

ANOMALIES ASSOCIATED WITH OXYDEMETON-METHYL 259

development, three of which involved congenital heart disease, Angelman (1961) found no family history of birth defects and suggested that the combination of defects represented a syndrome due to an adverse environment between the first and second month of pregnancy, when the neural tube, optic vesicle, and the heart are in an active state of differentiation.

It is unlikely that doxylamine (Bendectin) was the cause of the anomalies ob- served. Seven separate cohort studies found no teratogenic effects despite wide- spread use of the drug in the first trimester of pregnancy, while weak associations between use of the drug and encephalocele, esophageal atresia, and cardiac de- fects have been reported but were not statistically significant (Holmes, 1983). Furthermore, exposure at 9 weeks of fetal age could not lead to this group of malformations even if doxylamine were a potent teratogen.

Pesticide applicators who were exposed for at least 12 hr a week to organo- phosphate pesticides, including oxydemeton-methyl, had higher rates of chroma- tid breaks in the spraying season than in the winter (Yoder et al., 1973). Chro- mosome aberrations have also been found in workers who manufacture organo- phosphate pesticides (Kiraly et al., 1979), and in persons who have been severely poisoned by organophosphate pesticides (Bao et al., 1974).

Of the three insecticides involved in this case, the reproductive effects of ox- ydemeton-methyl are the best documented. The carbamate methomyl has not been found to be a mutagen in Salmonella typhimurium or Escherichia coli (Moriya et al., 1983), but there are possible metabolites of methomyl which are mutagenic (Blevins et al., 1977). The mutagenicity of mevinphos is equivocal. The compound has not been found to be mutagenic in Salmonella typhimurium (Car- ere et al., 1978), but it has been found to induce sister chromatid exchange in human lymphoid cells in vitro (Sobti et al., 1982).

Oxydemeton-methyl is a toxic organophosphate insecticide with an acute LDs0 of 47 mg/kg (Gaines, 1969). It is a mutagen in Escherichia coli (Mohn, 1973; Wild, 1975), Salmonella typhimurium (Pandita, 1983), and Saccharomyces cervisiae (Wild, 1975). It is slightly mutagenic in the sperm of an insecticide-resistant strain of Drosophila melanogaster (Vogel, 1974) and causes increased sister chromatid exchanges in cultured hamster cells (Chen et al., 1982). Two studies have found that there is a significant dose-related increase in the ratio of normochromatic to polychromatic erythrocytes in the bone marrow of mice dosed with 1 to 15 mg/kg oxydemeton-methyl (Pandita, 1983; Vaidya and Patankar, 1980). The compound caused a dose-related increase in the induction of sister chromatid exchanges (Pandita, 1983) and a dose-related induction of chromatid and isochromatid breaks (Vaidya and Patankar, 1980) in human lymphocytes in vitro.

There is little published data on the teratogenic potential of the three insecti- cides. We found only a single report, which describes a woman who was 5 months pregnant who attempted suicide with a 12-g dose of oxydemeton-methyl. She became severely ill, but delivered a normal infant (Carrington da Costa et al., 1982). The author observed that the pregnancy was too advanced to expect a teratogenic effect.

A rat inhalation study was done with methylsystox, a compound similar to oxydemeton-methyl (Gofmekler and Khuriev, 1971). Rats exposed to 0.0007 mg/

260 ROMERO, BARNETT, AND MIDTLING

m 3 and higher doses during their entire pregnancy produced fetuses with a higher incidence of developmental anomalies, principally a change in the dimension of the cerebral ventricles.

The teratogenicity studies required by federal and California state pesticide laws have not been published. Five such manufacturer-commissioned studies were obtained from state and federal agencies.

One of these studies found a teratogenic effect when Long-Evans rats were fed oxydemeton-methyl at oral doses of 3 mg/kg/day over a 10-day period (Kroetling and Kaliner, 1985). There were a significant reduction in maternal weight gain, significantly more stunted fetuses, and significantly more hypoplasias of the ce- rebral hemispheres in treated fetuses than in the controls, This effect was not seen when the test was repeated. No adverse reproductive effects were found in three other studies. These evaluated the fertility of male mice and examined the off- spring of rabbits and rats.

A study of the effect of oxydemeton-methyl on the reproduction of two gener- ations of rats reports that the compound reduced fertility, decreased litter size, decreased viability of newborn, and caused histopathological changes in the tes- tes, namely, heightened vacuolization of the duct epithelia of the epididymis (Kroetling and Kaliner, 1985).

On the basis of the mutagenic effects of oxydemeton-methyl alone, Pandita (1983) concluded that "workers in the vicinity of manufacture and application of Metasystox-R should be examined cytogenetically to monitor any genetic damage caused by the pesticide."

Since the anomalies reported here cannot be attributed to doxylamine expo- sure, the present case is the first report of possible human abnormalities associ- ated with prenatal occupational exposure to oxydemeton-methyl. Exposure ap- pears to have occurred during the period of major human organogenesis. Overt maternal intoxication could have been responsible for the malformations.

It must be emphasized that this represents only a report of an association between this chemical and human abnormalities. Further studies to investigate whether a causal relationship exists may be warranted by this sentinel report.

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