Developmental neurotoxicity

Short- to medium-term exposures have shown neurotoxicity, developmental toxicity, immunotoxicity, and endocrine disruption to be relevant end-points, although the degree of each of these toxic end-points differs across the group as a whole. 

Short- to medium-term exposure has shown neurotoxicity, developmental toxicity, immunotoxicity, and endocrine disruption to be relevant end-points. Table 24 summarizes the critical studies for each compound and identifies NOAELs or LOAELs. The degree of each of the toxic end-points differs across the group as a whole. For example, tributyltin is well established as an aromatase inhibitor, and dibutyltin appears to have some potency also (exact characterization of the endocrine disrupting capacity of dibutyltin alone is difficult because of the presence of tributyltin as an impurity). Monobutyltin and mono- and dioctyltins have no aromatase inhibiting capacity in in vitro tests. No data are available for this end-point for the methyltins. 

Organotin Neurotoxicity Developmental toxicity Endocrine disruption Immunotoxicity... 

Data adequacy The key study was well designed, conducted, and documented used 20 human subjects and utilized a range of concentrations and exposure durations. Occupational exposures support the 8-h AEGL value. The mechanism of headache induction (vasodilation) is well understood and occurs following therapeutic administration of nitrate esters to humans. Animal studies utilized several mammalian species and addressed metabolism, neurotoxicity, developmental and reproductive toxicity, and potential carcinogenicity. ... 

PCBs with a more globular structure elicit effects similar to phenobarbital. These include induction of the isozyme CYP2B, carcinogenic promoter activity8 7 and neurotoxicity. Developmental neurotoxicity of PCBs in animals is consistent with findings in children and results in persistent behavioural and neurological effects, notably alterations in motor development and cognitive function.88 The... 

Manganese at micromolar concentrations has long been recognized as essential for the proper development and normal function of the nervous system [1,5,8,188]. Recent reports add to the already abundant knowledge of the role of Mn(II) in neurochemistry of the whole organism. A deficiency or an excess of Mn(II) causes severe neurotoxic developmental and functional effects [188-190]. Exposure to abnormal levels of Mn(II) in the developmental stages of life may cause the mature animal to exhibit ataxia or startle responses [191], susceptibility to seizures or epilepsy [192-194]. In these reports most of the effects have been shown to correlate with or interrelate to levels of neurotransmitters or hormones, specific binding to receptors, abnormal diet, or stress [195-198]. 

Lead is a metallic element that occurs in nature. It is a notorious poison and exposure to lead reduces children s IQs. Lead exposure also causes an array of other health effects, including neurotoxicity, developmental delays, hypertension, impaired hearing acuity, impaired hemoglobin synthesis, and male reproductive impairment. ... 

The predominant toxic end-points vary among the different organotins and include neurotoxicity, reproductive and developmental toxicity, immunotoxicity,... 

No acute oral MRL was derived for methyl parathion because data regarding the most sensitive effect that was observed after acute oral exposure are conflicting. Increased pup mortality and altered behavior occurred in offspring of rats exposed to 1 mg/kg/day methyl parathion during, but no effects on pup survival or on sensitive electrophysiological indices of neurotoxicity were seen at virtually the same dose, 0.88 mg/kg/day, in a similar developmental toxicity study. 

Goldey ES, Tilson HA, Crofton KM. 1995. Implications of the use of neonatal birth weight, growth, viability, and survival data for predicting developmental neurotoxicity A survey of the literature. Neurotoxicol Teratol 17(3) 313-332. 

The data in animals are insufficient to derive an acute inhalation MRL because serious effects were observed at the lowest dose tested (Hoechst 1983a). No acute oral MRL was derived for the same reason. The available toxicokinetic data are not adequate to predict the behavior of endosulfan across routes of exposure. However, the limited toxicity information available does indicate that similar effects are observed (i.e., death, neurotoxicity) in both animals and humans across all routes of exposure, but the concentrations that cause these effects may not be predictable for all routes. Most of the acute effects of endosulfan have been well characterized following exposure via the inhalation, oral, and dermal routes in experimental animals, and additional information on the acute effects of endosulfan does not appear necessary. However, further well conducted developmental studies may clarify whether this chemical causes adverse developmental effects. 

Public concern about PBDE levels in the environment was heightened when it was shown that a sharp increase in the concentration of certain PBDEs had occurred in human breast milk over only a 10-year period (Meironyte et al. 1999 Noren and Meironyte 2000), and the levels of exposure in some infants and toddlers were similar to those shown to cause developmental neurotoxicity in animal experiments (Costa and Giordano 2007). As a result of these concerns, the majority of commercial PBDE mixtures have been banned from manufacture, sale, and use within the European Union. 

Costa, L.G. and Giordano, G. (2007). Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants. Neurotoxicology 28, 1047-1067. 

Additional animal studies of trichloroethylene following intermediate-duration oral exposure are necessary to further define dose-response relationships. Because developmental neurotoxicity appears to be a sensitive end point, a focus on this end point would be useful. Animals studies following intermediate-duration dermal exposure are necessary. These studies would indicate whether targets following dermal exposure differ compared to inhalation and oral exposure. 

Human toxicity Acute effects Carcinogenicity Genotoxicity/mutagenicity Developmental Teratogenicity/mutagenicity Neurotoxicity Endocrine disruption... 

The priority effects are carcinogenicity, mutagenicity, reproductive or developmental toxicity, endocrine disruption and neurotoxicity. Human toxicity is broader than priority effects, including acute toxicity, systemic toxicity (organ effects), immune system effects and skin/eye/respiratory damageaswellasthepriority effects. And toxicity as T includes both human toxicity and ecotoxicity. 

After a single dermal exposure to waste from the reclamation of a Fyrquel hydraulic fluid that may have been contaminated with tri-or/7 o-cresyl phosphate (TOCP), no apparent signs of neurotoxicity were observed in calves of 10 cows that manifested neurotoxicity just after the birth of the calves. The cows were apparently also exposed orally concurrent to the dermal exposure (Julian et al. 1976). No intermediate- or chronic-duration dermal studies examining developmental effects in animals were located. 

As hydrogen sulfide is a neurotoxic agent, an inhalation study examining potential developmental neurotoxicity is needed. Such studies should include a battery of tests to examine the function of the nervous system in the offspring of animals exposed to hydrogen sulfide during gestation or for various periods before adulthood. 

The American Petroleum Industry is currently sponsoring research on the toxicology of hydrogen sulfide. These studies include examinations of neurotoxicology, reproductive and developmental toxicology (including developmental neurotoxicity), and the development of a PBPK model. 

The mechanisms of developmental National Institute of neurotoxicity (rat) Environmental Health... 

Davis MJ. 1990. Risk assessment of the developmental neurotoxicity of lead. Neurotoxicology 11 285-292. 

Guilarte TR. 1997. Glutamatergic system and developmental lead neurotoxicity. Neurotoxicology 18(3) 665-672. 

In spite of the great effort and advances made on in vitro testing, we are still far to have alternative methods robust enough to cover developmental, neurotoxic, reproductive, or carcinogenic potential for the substances evaluated. However the use of some distinct approaches may cover a great part of the potential toxic effects of some environmental pollutants. 

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