Inhibitor Report for: Methyl-demeton

Organophosphates, a widely used class of insecticidal compounds, have been shown to cross the placental barrier, and thus potentially affect the developing fetus. This study compared the maternal and fetal effects, including cholinesterase inhibition, following gestational exposure to six organophosphates: tribufos, oxydemeton-methyl, azinphos-methyl, fenamiphos, isofenphos, and fenthion in the Sprague-Dawley rat. All test compounds were administered via oral gavage on gestation days 6-15. Maternal cholinesterase activities (plasma, PChe; erythrocyte, RChe; and brain, BChe) were measured on gestation days 16 and 20, and fetal brain cholinesterase activity was measured on gestation day 20. Effects on gestational parameters (clinical signs, food consumption, and body weight) in adult rats, when observed, were only observed at the highest dose tested for each compound. The inhibition of maternal cholinesterase activities associated with these clinical findings was, for all compounds, always greater than 20%. Moreover, cholinesterase activities were inhibited at dose levels below that which elicited clinical effects. Statistically significant inhibition of at least two of the three cholinesterase enzymes (PChe, RChe, or BChe) was observed on gestation day 16, 24 h following exposure, with all of the organophosphates tested. By gestation day 20, the inhibition of cholinesterase activity was reduced; however, the high dose for all test compounds (except BChe in fenamiphos-treated dams) continued to demonstrate statistically significant inhibition of RChe and BChe. Despite significantly affected cholinesterase activity in the dams, no remarkable effects on fetal BChe were observed with any test compound. No embryotoxicity or teratogenicity were observed with any of the test compounds. These results demonstrate that for the six organophosphates tested: (1) inhibition of maternal cholinesterase activity was the most sensitive indicator of organophosphate exposure; (2) the level of cholinesterase inhibition associated with clinical findings was always greater than 20%; and (3) no effect on fetal cholinesterase activity (BChe) was observed, even at dose levels that continued to demonstrate significant inhibition of maternal cholinesterase activity.

Organophosphate (OP)-related systemic illnesses reported to the Worker Health and Safety (WH&S) Branch, and restricted OP-related agricultural use data reported to the Information Services Branch at the California Department of Food and Agriculture (CDFA) (now CAL-EPA) during 1984-1988 were used to assess factors associated with OP-related systemic illnesses. Counts of OP-related systemic illnesses (numerator), relative to OP-related use data (denominator), such as pounds applied, number of applications, and acres treated (pounds applied/acres treated), were analyzed by crop treated, season of application, method of application, geographic region, and by specific OP applied. A Relative Illness/Use Ratio (RIUR) was calculated by Poisson regression. The highest risk of systemic illness was associated with OP applications to fleshy fruit (mainly fruit trees) compared to all other crops combined (RIUR = 2.9, 95%CI = 2.2-3.9) using pounds applied in the denominator, followed by vegetables and melons (RIUR = 1.9, 95%CI = 1.4-2.4). Air applications resulted in higher RIURs for systemic illness than did ground applications (RIUR = 2.1, 95%CI = 1.7-2.5). Specific OPs that showed significantly elevated RIURs for systemic illness when compared to other OPs were Mevinphos (RIUR = 5.8, 95%CI = 5.0-6.8), Demeton (RIUR = 4.3, 95%CI = 2.6-7.1), Oxydemeton-Methyl (RIUR = 3.8, 95%CI = 3.0-4.9), Methamidophos (RIUR = 1.6, 95%CI = 1.2-2.0) and Azinphos-Methyl (RIUR = 1.3, 95% CI = 1.1-1.6).

Significant increase of sister-chromatid exchanges (SCE) in V79 cells treated with 2 organophosphorus pesticides (OPP), fenthion and oxydemeton-methyl, was observed. The other 7 compounds (6 OPP and 1 defoliant) namely, amaze, azinphos-methyl, bolstar, DEF-defoliant, fensulfothion, monitor and nemacur caused no increase of SCE frequencies at the doses tested. All the compounds except fensulfothion and oxydemeton-methyl induced cell-cycle delay in varying degrees. Cell-cycle delay caused by an OPP was found to be dose-dependent. Based on these data as well as others reported, it would appear that OPP which induce no SCE increase and no or slight cell-cycle delay could be considered as good candidates to substitute the pesticides that have been found to be harmful to the environment.

Organophosphates, a widely used class of insecticidal compounds, have been shown to cross the placental barrier, and thus potentially affect the developing fetus. This study compared the maternal and fetal effects, including cholinesterase inhibition, following gestational exposure to six organophosphates: tribufos, oxydemeton-methyl, azinphos-methyl, fenamiphos, isofenphos, and fenthion in the Sprague-Dawley rat. All test compounds were administered via oral gavage on gestation days 6-15. Maternal cholinesterase activities (plasma, PChe; erythrocyte, RChe; and brain, BChe) were measured on gestation days 16 and 20, and fetal brain cholinesterase activity was measured on gestation day 20. Effects on gestational parameters (clinical signs, food consumption, and body weight) in adult rats, when observed, were only observed at the highest dose tested for each compound. The inhibition of maternal cholinesterase activities associated with these clinical findings was, for all compounds, always greater than 20%. Moreover, cholinesterase activities were inhibited at dose levels below that which elicited clinical effects. Statistically significant inhibition of at least two of the three cholinesterase enzymes (PChe, RChe, or BChe) was observed on gestation day 16, 24 h following exposure, with all of the organophosphates tested. By gestation day 20, the inhibition of cholinesterase activity was reduced; however, the high dose for all test compounds (except BChe in fenamiphos-treated dams) continued to demonstrate statistically significant inhibition of RChe and BChe. Despite significantly affected cholinesterase activity in the dams, no remarkable effects on fetal BChe were observed with any test compound. No embryotoxicity or teratogenicity were observed with any of the test compounds. These results demonstrate that for the six organophosphates tested: (1) inhibition of maternal cholinesterase activity was the most sensitive indicator of organophosphate exposure; (2) the level of cholinesterase inhibition associated with clinical findings was always greater than 20%; and (3) no effect on fetal cholinesterase activity (BChe) was observed, even at dose levels that continued to demonstrate significant inhibition of maternal cholinesterase activity.

Organophosphate (OP)-related systemic illnesses reported to the Worker Health and Safety (WH&S) Branch, and restricted OP-related agricultural use data reported to the Information Services Branch at the California Department of Food and Agriculture (CDFA) (now CAL-EPA) during 1984-1988 were used to assess factors associated with OP-related systemic illnesses. Counts of OP-related systemic illnesses (numerator), relative to OP-related use data (denominator), such as pounds applied, number of applications, and acres treated (pounds applied/acres treated), were analyzed by crop treated, season of application, method of application, geographic region, and by specific OP applied. A Relative Illness/Use Ratio (RIUR) was calculated by Poisson regression. The highest risk of systemic illness was associated with OP applications to fleshy fruit (mainly fruit trees) compared to all other crops combined (RIUR = 2.9, 95%CI = 2.2-3.9) using pounds applied in the denominator, followed by vegetables and melons (RIUR = 1.9, 95%CI = 1.4-2.4). Air applications resulted in higher RIURs for systemic illness than did ground applications (RIUR = 2.1, 95%CI = 1.7-2.5). Specific OPs that showed significantly elevated RIURs for systemic illness when compared to other OPs were Mevinphos (RIUR = 5.8, 95%CI = 5.0-6.8), Demeton (RIUR = 4.3, 95%CI = 2.6-7.1), Oxydemeton-Methyl (RIUR = 3.8, 95%CI = 3.0-4.9), Methamidophos (RIUR = 1.6, 95%CI = 1.2-2.0) and Azinphos-Methyl (RIUR = 1.3, 95% CI = 1.1-1.6).

The purpose of this study was to assess the embryotoxic, fetotoxic, and teratogenic potential of METASYSTOX-R (MSR) in the rat. Furthermore, the study was designed to determine if maternally toxic doses of MSR altered fetal brain acetylcholinesterase (AChE), compromised neonatal survival, growth, and development, or affected neurobehavioral development. Inseminated female rats (45/dose group) received single daily oral doses of 0, 0.5, 1.5, or 4.5 mg/kg of MSR from Days 6 to 15. Dose groups were subdivided into three termination phases: Phase I, 5 females terminated on Day 16 of gestation; Phase II, 28 females terminated on Day 20 of gestation; Phase III, 12 females terminated on Day 21 postpartum. MSR produced a dose-related reduction in maternal plasma (30-72%), red blood cell (18-56%), and brain (21-68%) cholinesterase (ChE) activity, when measured on Day 16 of gestation. The high dose of MSR significantly (p less than or equal to 0.05) reduced food consumption, suppressed body weight gain, and produced tremors in 98% of the dams. MSR administered at maternally toxic doses as high as 4.5 mg/kg was devoid of embryotoxic, fetotoxic, and teratogenic effects. Fetal brain AChE was not substantially different from control for any dose level in Day 20 fetuses. Furthermore, neonatal survival, growth, and development were unaffected and an extensive neurobehavioral testing scheme demonstrated no alteration of sensory or reflex functions, maze learning ability, or open field activity for neonates.

Significant increase of sister-chromatid exchanges (SCE) in V79 cells treated with 2 organophosphorus pesticides (OPP), fenthion and oxydemeton-methyl, was observed. The other 7 compounds (6 OPP and 1 defoliant) namely, amaze, azinphos-methyl, bolstar, DEF-defoliant, fensulfothion, monitor and nemacur caused no increase of SCE frequencies at the doses tested. All the compounds except fensulfothion and oxydemeton-methyl induced cell-cycle delay in varying degrees. Cell-cycle delay caused by an OPP was found to be dose-dependent. Based on these data as well as others reported, it would appear that OPP which induce no SCE increase and no or slight cell-cycle delay could be considered as good candidates to substitute the pesticides that have been found to be harmful to the environment.