Total, dimethyl, and diethyl DAP in urine were all significantly associated with an increased number of abnormal reflexes and the proportion of neonates with more than three abnormal reflexes . Interestingly, the association differed depending on the age at which the Brazelton Neonatal Behavioral Assessment Scale was administered. The association was negative in neonates examined after age 3 d but was unexpectedly positive in infants assessed within the first 3 d of life . An ecological study of 4- to 5-yr-old Yaqui children in Mexico demonstrated decreases in stamina, hand–eye coordination, and recall and an almost complete inability to draw a person in children living in an agricultural valley who were exposed to multiple pesticides compared to children from families living in the foothills who were employed in ranching . Notably, the two groups shared genetic, cultural, and social traits and differed mostly in type of parental employment and the use of pesticides and chemical fertilizers. Several other cohorts have been established for the investigation of the effects of in utero OP pesticide exposure on pregnancy and neurodevelopmental outcomes. Only pregnancy outcomes have been reported for these cohorts as well as for women of the CHAMACOS project. In the CHAMACOS cohort, DAP metabolites were associated with a significant increase in head circumference and a marginally significant increase in birth length . Only dimethyl phosphate, and not DEP, metabolites and cord cholinesterase activity were significantly associated with decreased length of gestational duration. In marked contrast, in a cohort of African-American and Dominican women from New York, cord blood concentrations of chlorpyrifos were a significant independent predictor of decreased birth weight and birth length . Ethnic-specific regressions indicated that the effect on birth weight was statistically significant only among African-American women, whereas the effect on birth length was significant only in Dominican women. An extension of this study confirmed the significant association between cord plasma chlorpyrifos and diazinon levels and decreased birth weight and length in a somewhat larger cohort,vertical growing systems but it was unable to detect an association with insecticide concentrations in maternal personal air during pregnancy.
Notably, although the associations between cord plasma concentrations of chlorpyrifos and diazinon were highly significant in children born before the US EPA started to phase out residential use of these pesticides, they were no longer detected in children born after. However, only cord plasma chlorpyrifos, but not diazinon, levels were significantly decreased in the relevant period. In a different cohort of pregnant women in New York, no association was detected between self-reported pesticide use during pregnancy, urinary levels of TCPy, or pyrethroid metabolites obtained during the third trimester and birth weight, length, head circumference, or gestational age . However, when maternal activity of the phase-II detoxifying enzyme paraoxonase 1 activity was accounted for, maternal urinary chlorpyrifos metabolite levels were associated with a small, but significant, decrease in head circumference. Most of the enzymes involved in the metabolism, activation, and detoxification of OP pesticides and other chemicals discussed here exhibit polymorphisms that greatly influence enzyme activity. This study represents one of the rare examples where at least one of these polymorphisms was accounted for. Notably, urinary levels of pesticide metabolites are highly variable, and measurements obtained at three different time-points show significant within-person variability . Therefore, one or two spot-urine samples are unlikely to provide a reliable measure of pesticide exposure throughout pregnancy. This may partially explain the inconsistent findings regarding birth outcomes in the aforementioned studies. Whether cord plasma or meconium concentrations constitute a more reliable measure remains to be established.Chronic exposure of rats to the pesticide rotenone has been found to constitute an animal model of Parkinson’s disease that reproduces the typical biochemical, molecular, anatomical, and behavioral findings in Parkinson’s disease . These include binding to complex I in the brain, selective nigrostriatal dopaminergic degeneration with relative sparing of the dopaminergic fibers in medial aspects of striatum, cytoplasmic inclusions containing ubiquitin and α-synuclein resembling the Lewy bodies associated with Parkinson’s disease, and hypokinesia and rigidity.
Notably, rotenone is a “natural” plant-derived compound that even organic farmers use on vegetable crops. Several epidemiological studies have suggested an association between agricultural work, which usually includes pesticide exposure, or pesticide exposure per se and idiopathic Parkinson’s disease , although others have found only suggestive evidence for such an association or have found no association . There is increasing evidence that occupational exposure to certain pesticides increases the risk of several cancers, including cancers of the brain and lungs , acute myeloid leukemia , and possibly multiple myeloma . Children may be particularly sensitive to the carcinogenic effects of pesticides, as suggested by numerous reports of associations between residential pesticide exposure and childhood cancers—particularly brain cancer and leukemia but also Wilm’s tumor, Ewing’s sarcoma, and germ cell tumors . Because cholinergic nerves in the vagi provide the major neural control of airway tone and reactivity, it seems plausible that OPs could induce airway hyperreactivity and asthma . Seven days after a single subcutaneous injection of 70 mg/kg of chlorpyrifos, vagally induced bronchoconstriction was found to be potentiated in guinea pigs in the absence of AChE inhibition . This effect was accompanied by decreased M2 muscarinic receptor function, whereas M3 receptor function was not affected. Similar results were obtained 24 h after administration of 1 or 10 mg/kg of parathion and 0.75 or 75 mg/kg of diazinon, although only the higher doses inhibited AChE . Intraperitoneal administration of parathion to guinea pigs increased lung resistance and mucus secretion and induced pulmonary edema . These broncho-obstructive effects were demonstrated to depend on the biotransformation of parathion by P450 enzymes. Even doses that did not increase lung resistance were able to induce airway hyper responsiveness not only to ACh but also to histamine. The latter was prevented by atropine, suggesting the involvement of a cholinergic mechanism. In the Agricultural Health Study, data collected on more than 20,000 farmers indicated that use of the OPs malathion and chlorpyrifos dose-dependently increased the risk of wheeze, and parathion also carried an elevated OR . It remains to be established whether OP pesticides at environmental exposure levels increase the risk of asthma and asthma-like symptoms.
OCs comprise a diverse group of synthetic chemicals that include not only pesticides but polychlorinated biphenyls , polybrominated biphenyls, polychlorinated dibenzofurans , and polychlorinated dibenzodioxins . OC pesticides include 1,1,1-trichloro- 2,2-bisethane ; lindane and other hexachlorocyclohexanes; cyclodienes such as dieldrin, chlordane, and heptachlor; and hexachlorobenzene. Many OCs—particularly the more heavily chlorinated ones—resist biotic and abiotic degradation and are lipophilic; therefore, they not only bio-accumulate in all parts of the environment,curing marijuana but are bio-concentrated from one trophic level to the next. PCDDs and PCDFs are tricyclic aromatic compounds. Because they can be substituted with between one and eight chlorine atoms, there are potentially 75 different PCDD and 135 PCDF congeners . However, the actual number present in biotic samples is much lower, and mainly 2,3,7,8-substituted congeners are detected. The most toxic congener is 2,3,7,8-tetrachlorodibenzo-p-dioxin , often referred to simply as “dioxin,” whereas the PCDDs are called dioxins. There are 209 possible PCB congeners, which differ in the degree of chlorination and the position of the chlorine atom; however, depending on the species and its trophic level, only between 50 and 150 congeners are detectable in biotic samples . Whereas PCDDs and PCDFs have rigid planar structures, the two rings of PCB molecules are joined by a single carbon–carbon bond, thus allowing axial rotation of the benzene rings. This freedom is restricted by the number and positions of the chlorine substituents and decreases from nonortho via mono-ortho to di-, tri-, and tetraortho PCBs. Planar PCBs exhibit the greatest resemblance to the dioxins. Whereas PCBs and polybrominated biphenyls were purposely produced for use as dielectric fluid in transformers and capacitors, hydraulic fluid, plasticizers, and fire retardants, PCDD/Fs arise as byproducts of thermal and industrial processes, particularly via incineration of municipal and hazardous waste. PCBs were produced in the United States from the 1920s until they were banned in 1977, with peak production occurring during the 1960s and 1970s. Historical global production of PCBs is conservatively estimated at 1.3 million tons, which were used almost exclusively in the Northern hemisphere . Emissions of PCBs were estimated to be in the range of 440 and 92,000 tons , and other data strongly have suggested that actual emissions were closer to the upper estimate . The environmental residence times of two of the major PCB congeners, PCBs 153 and 180, were recently estimated to be 110 and 70 yr, respectively ,suggesting that although the production of PCBs was halted approx 30 yr ago, exposure will continue for decades, if not centuries.Because persistent OCs are lipophilic, resist metabolism and bio-degradation, and bio-accumulate to similar extents in various biota, humans are simultaneously exposed to complex mixtures of these compounds. However, the precise nature of the mixture depends on various factors such as solubility, volatility, and rates of degradation as well as dietary and other lifestyle factors and geographic location. For the purposes of risk assessment and regulatory action, the concept of toxic equivalency factors has been developed . It is based on evidence that PCDDs, PCDFs, and certain PCBs exert their toxicity via binding to the aryl hydrocarbon receptor and subsequent induction of gene expression, particularly of various cytochrome P450 isozymes. The TEF concept assumes that the combined effects of these OCs can be predicted by a model of concentration addition. TEF values can then be used to calculate toxic equivalent concentrations by multiplying the concentrations of each PCDD, PCDF, or PCB by its TEF. Commonly, either the World Health Organization TEQs or the international TEQs developed by the NATO are used.
Inhalation of airborne OCs, stemming mostly from municipal and industrial incinerators and open burning of household trash, and dermal exposure make comparatively minor contributions to exposure. More than 90% of current exposure to background levels of PCBs and DDT and its metabolite dichlorophenyl dichloroethylene is believed to come from the dietary intake of contaminated foods—particularly dairy products, meat, and fish . Fish can contribute 75% or more of total PCDD/F and PCB TEQ ingestion in countries with high fish consumption , and in several studies, intake of fish—particularly from highly contaminated waters like the Great Lakes or the Baltic sea— has shown a significant association with serum concentrations of PCBs and their metabolites and PCDD/Fs . Notably, the traditional diet of many Arctic populations includes substantial amounts of marine foods, including sea mammals. Although OCs have been produced and used primarily in the lower and middle latitudes of the Northern hemisphere, long-range transport via the predominantly northward flow of rivers and ocean and atmospheric currents results in high exposure levels in the Arctic . Because of their lipophilicity and resistance to bio-degradation, many OCs bio-accumulate in fatty tissues and are bio-magnified in the aquatic food webs. Their consumption is associated with concentrations of PCBs and other OCs in serum, breast milk, and adipose tissue samples obtained from various Inuit populations that are up to fivefold higher than in other North American or European populations . In the United States, daily dietary intake of dioxin TEQs in the early 1990s was estimated to be 0.3 to 3.0 pg/kg body weight TEQs for an adult who weighed 65 kg . Estimates in eight European countries during the 1990s varied between 65 pg I-TEQ/d in the Netherlands and 210 pg I-TEQ/d in Spain, which is equivalent to 1 to 3 pg I-TEQ/kg body weight/d assuming a body weight of 70 kg . A more recent market basket study conducted in Finland on almost 4000 samples representing 228 food items, combined with results of a 1997 dietary survey, produced a similar estimate of 115 pg WHOTEQ/d, or 1.5 pg WHO-TEQ/kg body weight using an average weight of 76 kg . Up to threefold higher values for mean daily PCB and dioxin intake estimates have been reported for children . In most of the countries,the contributions of dioxins and dioxin-like PCBs to total TEQs were roughly equal, varying between approx 40 and 60%. Together, these data indicate that the daily intake of dioxin TEQs of many Europeans exceeded and probably still exceeds the TDI of 1 to 4 pg/kg/d recommended by the WHO .