Health Impact Of Long-term Exposure To Organophosphorus Pesticides

Organophosphorus Pesticides(OPs) are produced in large scale and are widely used because of high efficacy relatively, low toxicity and low levels of leftover. With the emphasis on prevention and cure of occupational poisoning , the mechanism, diagnosis, and treatment of acute poisoning of OPs have been highly recognized and improved. However, workers who are chronically exposed to low levels of OPs also suffer health problems. The purposes of this study are: 1) to explore dose-response relationships between low level exposure to OPs and adverse effect in different accumulating doses, 2) to explore the susceptible genotype, and 3) to provide a reliable, theoretical basis on the prevention of toxic effects from low level exposure to OPs, especially the susceptible workers. so that the occupational safety of population exposed to OPs is considered, and a foundation was laid for formulating the reciprocal precautionary strategy.Firstly, the external and internal dose were evaluated through the environmental monitoring data from multiple years on air OPs concentration and population health status in a pesticide factory in Shanghai. Subsequently, a multi-analysis of responses to different accumulating doses on some biomarkers and health effects was made. Then, the relationship between gene polymorphism and health effects was explored, in order to find any significant effects on health with long-term exposure to OPs.Part 1 Exposure assessment of Occupational OPsExternal dose: Based on the plant production and air quality data of the workshop, the main products of the plant were methamidophos, rogor, dichlorovos and other OPs. The concentration of OPs in the air was found to be exceeding the national standard in early 1970s. Since then, the concentration has decreased yearly and was controlled under the national standard after 1983(<1mg/m~3). So the present study is to consider the difference of dose before and after the year of 1983 and investigate the health effect of different exposure dose and accumulating dose respectively .Internal dose: 161 workers from pesticide plant were selected as direct exposure group while 122 service persons as indirect exposure group . Five kinds of urinary metabolites (DMP, DEP, DETP, DMDTP, DEDTP) from both groups were determined using gas chromatography . The result was that the workers were exposed to more than one type of OPs The concentration of DMP and DETP of those in the directly exposed group was higher than that of indirectly exposed group. Working in different workshop may have different urinary metabolites, while the type of job influenced the concentration of urinary metabolites . The consistency study of external and internal dose indicated that the external and internal dose can be an indicator of OPs exposure .Part 2 Study on early biomarker and health effectsThe measurement of activity of esterase : 241 workers of direct exposure group ,161 service persons of indirect exposure group and 150 workers in another plant without any records of occupational exposure were studied. The serum activity of four kinds of esterase were measured respectively . Exposure to OPs may inhibit the activity of these esterases . The inhibition of AchE was related to workshop and the type of work , the finding was consistent with the result of multi-variance analysis of acetylcholinesterase (AchE) , indicating exposure of various OPs may inhibit the AchE remarkably, with relation to exposure dose .The inhibition of carboxylesterase (CarbE) activity was related to the exposure time, especially in the low-dose of the work years from 5 to 10 which tends to recover. Besides, there was a dose-response relationship between the external exposure dose and CarbE activity. Therefore, the inhibition of CarbE can be an early biomarker of long-term exposure to OPs.Signs and symptoms: The occupational exposure history and signs were collected through questionnaires and medical examinations. The weighting and total score of the signs , such as neuromuscular system , respiratory system , circulatory system and digestive system, was calculated , and abnormal rate of medical examination , such as count of white blood cell, hemoglobin, electrocardiogram , abdominal region of B-mode ultrasonography and bloodpressure , were also calculated. It was found that the weighting and total systems score in direct and indirect exposure group was higher than that in control group , and there was a dose-response relationship between the internal exposure dose and digestive system score . A higher percentage of abnormal hemoglobin was found in the workers in direct exposure group , in correlation with exposure time. The workers (working time 5-10 years) in direct exposure group showed a higher percentage of abnormal hemoglobin level, and there was dose-response relationship between the percentage of abnormal hemoglobin and accumulating external exposure dose(liner-liner association analysis P<0.05). Besides this, some system scores and the percentage of abnormal hemoglobin were related to AchE activity regarded as an exposure dose. There was negative correlation between the activity of AchE and signs scores according to correlation analysis. It showed a increasing trend of signs scores and percentage of abnormal hemoglobin following the decrease f AchE activity.Survey on cancer and death cause: To investigate the death cause and mortality of cancer of OPs exposed workers and to study the relationship between low dose occupational OPs exposure and cancer by the analysis of 22 years death data in a pesticide factory. A cohort including 2270 workers employed for at least 1 year before Jan 1, 1983 and a sub-cohort of 1018 of them worked at OPs exposed workshop was studied. The study was followed up from Jan 1, 1983 to Dec 31 , 2004 . The death cause spectrum of OPs exposed workers was similar to that in reference population, but higher mortality of malignant tumor was found in pesticides ,exposed workers, SMR for all cancer, and malignant cancer were 120.2 and 119.6 respectively. SMR for malignant tumor of bladder, lung and stomach cancer were 303.7, 141.2, and 137.5 respectively (P<0.01). Chi-square test showed tumor mortality of exposed workers was higher than that of non-exposed workers (P<0.01), indicating the risk of malignant tumor death increased with exposure to OPs.Part 3 Effects of the genetic polymorphism of esterases on health status Detection of genotype: The genotypes of enzymes(PON192, PON55, BchE, P450, NAT2) and the polymorphic distribution were detected using 7900 genotype detecting system and CMOS Chip technique. The abnormal allele frequency of PON192, PON55 and BchE was37.8%,1.9% and 13.7% respectively, while the abnormal homozygote frequency of PON192 and BchE was 15.0% and 1.6%. with no abnormal homozygote of PON55. The genotypes of all enzymes reached Hardy-Weinberg balance.Effects of the genetic polymorphism: Effects of the genetic polymorphism of metabolic enzyme on urinary metabolites, activity of esterases, signs and symptoms were analyzed. Polymorphism of P450 metabolic enzymes (CYP1A2 , CYP2E1) influenced the concentration of urinary metabolites (DEP , DEDTP). The genotypes of PON192 and PON55 influenced the activity of PON. The genotype of PON-192~* AA showed low activity, and the activity of genotype of PON55 (ML) was low too. Lower activity of the same genotype of PON192 and PON-55 (working duration less than 20 years) was found, while the BchE activity of workers more than 20 working years had the higher inhibition . The relationship between paraoxonase (PON), butyrylcholinesterase(BchE) and exposure dose was found after control of the influence of the gene polymorphism. The activity of PON was lowest in the workers with genotype of PON192~*AA+PON55~*ML+BchE~*KK, and the AchE activtity was lower while signs scores was higher. The genotype of PON192~*AA +PON55~*ML+BchE~*KK was most sensitive. The liner regression analysis showed the polymorphism of PON and BchE affected the activity of AchE , confirming the gene polymorphism affected health effects.Summary:The environmental mornitoring data showed significant difference before and after the year of 1983 as comparable high and low exposure dose to organophosphates pesticide. The result of urinary metabolites confirmed variation of exposure of OPs. There was consistency between external and internal exposure dose .Exposure to OPs influenced the carboxylesterase activity of Carb, PON, BchE and AchE . and exposure of various organophosphates pesticide may inhibit the AchE remarkably , with relation of exposure dose . Exposure to organophosphates in the low-dose of the work year from 5 to 10 affected CarbE and hemoglobin mostly . It was found that the signs scores and the abnormal rate of hemoglobin in exposure group was higher . There was a dose-responserelationship among urinary metabolites , carboxylesterase activity and health effect.3. The death cause of pesticides exposed workers was similar to that of reference population, but higher mortality of malignant tumor were found in pesticide exposed workers , SMR for cancer malignant tumor of bladder, lung and stomach cancer were 303.7, 141.2, and 137.5 respectively. Tumor mortality of exposed workers was higher than non-exposed workers (P<0.01) . and the risk of malignant tumor and tumor death increased with the increase of accumulating exposure dose .4. The genetypes of PON192 and PON55 influenced the activity of PON. Lower activity of the same genetype of PON192 and PON-55 (working time less than 5 years) was noted . The genetype of PON192~*AA +PON55~*ML+BchE~*KK was most sensitive, providing the theoretical basis for screening the susceptible population .