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10 DRINKING WATER AND HEALTH ALDICARB propanal, 2-methyl-2-(methylthio), [(methyl amino) carbonyl]oxime CASNo.11606-3 CH2 o 11 CH3S-C—CH = NOCNHCH3 1 CH2 Aldicarb was evaluated in the first volume of Drinking Water and Health (National Research Council, 1977, pp. 635-643~. The following material, which became available after the 1977 report was prepared, updates and, in some instances, reevaluates the information contained in the previous review. Also included are some references that were not assessed in the earlier report. METAL O LI SM Preliminary studies by Hurst and Dorough (1978, abstract) indicate that aldicarb, which is an inhibitor of acetylcholinesterase, inhibits certain car- boxyesterases that play a role in the hydrolytic detoxification of this pesti- cide. Such anticarboxyesterase activity could enhance the toxicity of this agent. By administering radiocarbon-labeled aldicarb to bile-cannulated rats, Marshall and Dorough (1979) demonstrated that an oral dose is com- pletely absorbed. In their experiment, approximately 28~o of the dose ap- peared in the bile within 24 hours; 64~o was excreted in the urine. Reduced acetylcholinesterase activity was observed in the brain and liver of rat fetuses for as long as 24 hours after doses of 0.01 or 0.10 mg/kg body weight (bw) were administered orally to the dams (Cambon et al., 1979~. REALTH ASPECTS Observations in Humans Peoples et al. (1978) reviewed 38 reports of occupational illnesses that ap- parently resulted from exposure to aldicarb. These reports were obtained from the registry for the State of California, where the product is available only as a granular formulation. The symptoms described in the documents were consistent with those expected for a carbamate insecticide: dizziness, blurred vision, constricted pupils, nausea, and abdominal pain. Virtually all incidents involved employees who handled, loaded, or applied aldicarb.

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Toxicity of Selected Contaminants 11 Several of them were admitted to the hospital. Depressed plasma cholines- terase levels were observed in some patients. Although some of the subjects were reported as having been very ill, recovery, which was rapid and com- plete, was aided in some cases by the administration of atropine. A committee of the National Research Council (1982) found no evidence that long-term health effects resulted from short-term exposure to a variety of anticholinesterase compounds. That committee did not specifically re- view aldicarb, which is a member of that broad class of chemicals. None- theless, this conclusion provides reassurance that short-term exposure to aldicarb is unlikely to produce long-term adverse effects on human health. Observations in Other Species The committee found no reports that extended or amplified previous dis- cussions on the acute or chronic effects of aldicarb in animal species. Mutagenicity Normal cultured skin cells from humans were treated with aldicarb. No breaks in DNA were detected (Blevins et al., 1977a,b). A transplacental host-mediated hamster cell assay was used to study the ability of aldicarb to induce morphological transformation in fetal cell cul- tures. These cultures were also examined for growth in soft agar (0.3~o) and for their ability to induce tumors in nude mice. Negative results were obtained with aldicarb (Quarles et al., 1979b). Negative results were also obtained in a test with bone marrow erythrocyte micronuclei from mice. However, because of the extreme toxicity of aldicarb (i.e., an LDso of 1 mg/kg bw), it could not be administered at high doses (Seller, 1977~. The evidence indicates that aldicarb is nonmutagenic in several assays that allow for the detection of genotoxicity. The results from the mouse micronucleus test remain inconclusive because of the toxicity of the com- pound. Carcinogenicity Aldicarb was tested for carcinogenicity in Fischer 344 rats and B6C3~ mice (National Cancer Institute, 1979~. The pesticide was administered to both the rats and the mice in their feed at doses of either 2 or 6 mg/kg. The animals were dosed for 103 weeks and sacrificed shortly thereafter. No evidence of carcinogenicity related to aldicarb was found in either sex of mice or rats. Because there was no indication of weight de- pression or early mortality, it is possible that a maximum tolerated dose was not used. Under the conditions of this bioassay, technical-grade aldicarb was not carcinogenic to either Fischer 344 rats or B6C3~ mice of either sex. Teratogenicity The committee found no data to evaluate.

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12 DRINKING WATER AND HEALTH CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level {SNARL) Chronic Exposure Long-term (2-year) feeding studies have been con- ducted in rats and dogs. The studies reviewed in the first volume of Drir~k- ing Water arid Health (National Research Council, 1977, pp. 635-693) es- tablished 0.1 mg/kg/day no-adverse-effect levels in both animal species. This resulted in the calculation of an acceptable daily intake (ADI) for aldicarb of 0.007 mg/liter. This value continues to be the recommended SNARL for chronic exposure. Work cited in the first volume indicated that the acute effects of aldicarb toxicity are readily reversible. Unless exposure is sustained, therefore, cumulative effects are unlikely. None of three long- term rodent studies on aldicarb provided evidence of a carcinogenic effect. In fact, no chronic toxicity of any type was observed. This may be attrib- uted to the limited maximum daily dose that could be given because of the potent anticholinesterase activity of aldicarb. Animal studies have pro- vided no indication that aldicarb has any untoward toxicity other than that associated with anticholinesterase activity. Since animal studies of sufficient duration have been conducted and since restrictions on dosage have been imposed by the intrinsic toxicity of the agent, it is unlikely that any further meaningful repeated exposure data will be forthcoming. The best judgment that can be made with the data in hand is that exposure of humans to doses of aldicarb that do not affect cholinesterase will not result in any adverse effects. CARBOFURAN 7-benzofuranol, 2,3~ihydr~2,2~imethyt-, methy~carbamate CAS No. 1563-6~2 OOCNHCH3 ~