Mixture Neurotoxicity

Though most environmental exposures are to mixtures, most developmental neurotoxicity studies have addressed only single chemicals. Only a very few have addressed the effects of mixtures and even fewer have reported quantitative data on concentrations and dose levels. Following is a review of the literature on the subject. 

Mercury Motor dysfunction Learning and memory disabilities 

Solvents Ethanol Attention deficits and behavioral disorders 

Styrene Memory impairment Decreased activity Behavioral disorders 

Toluene Speech and motor dysfunctions Learning disabilities 

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Triebig G. 1989. Occupational neurotoxicology of organic solvents and solvent mixtures. Neurotox Teratol 11 575-578. 

Monooctyltin No neurotoxicity reported in 90-day studies Teratogenicity appears to be low (NOAEL = 120 mg/kg body weight per day) based on one study on a monooctyltin/dioctyltin mixture at 67 33 No aromatase inhibition in vitro NOAEL = 0.87 (decreased thymus weight) mg/kg body weight per day (as MOTC/DOTC mixture 65 35 )... 

The database for monomethyltin is not conclusive for neurotoxic effects, and, therefore, a NOAEL could not be determined. However, on the basis of 90-day studies on monomethyltin/dimethyltin mixtures detailing histopathology, dose comparisons between studies on different mixtures suggest that dimethyltin is the predominant active ingredient, and, taking into account structure-activity relationships, it would be expected that the neurotoxicity of monomethyltin is lower than that of dimethyltin. 

Dimethyltin/monomethyltin neurotoxicity studies (2 x go day one drinking-water, one food) were performed using mixtures. The NOAEL is based on measured dimethyltin intake. Dimethyltin is assumed to be the more neurotoxic of the two. The suggested TDI for monomethyltin is therefore highly conservative. 

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. 

The stimulation of locomotor activity by MDMA and the importance of mesolimbic dopamine in this response reflect similarities with the prototype phenylethylamine stimulant, amphetamine. It is important to note that these parameters are frequently associated with rewarding aspects of drugs and drug abuse. Additionally, the behavioral profiles of MDMA and I E share certain characteristics with hallucinogen-Iike agents. This unique mixture of stimulus properties and neurochemical actions may contribute to a dangerous behavioral toxicity and neurotoxic potential for drugs like MDMA. 

Monsanto. 1987c. In vivo/in vitro neurotoxicity studies of Skydrol LD-4 in adult hens with mixtures of butyl diphenyl phosphate, dibutyl phenyl phosphate and tributyl phosphate. 

Mortensen A, Ladefoged O. 1992. Delayed neurotoxicity of trixylenyl phosphate and a trialkyl/aryl phosphate mixture, and the modulating effect of atropine on tn-ortho-to y phosphate-induced neurotoxicity. NeuroToxicology 13 347-354. 

The neurotoxicity of pure M-hexane (99%) has been compared to mixed hexanes (a mixture containing the -hexane isomers 2-methylpentane, 3-methylpentane, cyclohexane, methyl cyclopentane, and 2,3-dimethyl butane with approximately 1% -hexane) (IRDC 1981). The mixture was intended to be more representative of products used commercially. In this experiment, groups of Sprague-Dawley rats were exposed to -hexane alone (500 ppm), mixed hexanes (494 ppm) or -hexane plus mixed hexanes (992 ppm) daily for 6 months, 22 hours a day. No deaths occurred as a result of treatment. 

Neurological Effects. The major public health concern regarding -hexane exposure is the potential for the development of neurotoxicity. Occupational studies have documented that human exposure to -hexane can result in a peripheral neuropathy that in severe cases can lead to paralysis (Altenkirch et al. 1977 Yamamura 1969 Wang et al. 1986). The dose-duration relationship has not been well characterized in humans, but concentrations of 500 ppm and above, and exposure for 2 months or more have been associated with human neurotoxicity. Brief exposure to extremely high concentrations of w-hexane may cause signs of narcosis in humans prostration and coma have been observed in animals exposed to a mixture of hexanes at concentrations of 70,000-80,000 ppm (Hine and Zuidema 1970). At these levels, however, explosion and fire would be the main concern. 

Stoltenburg-Didinger G, Altenkirch H, Wagner M. 1990. Neurotoxicity of organic solvent mixtures Embryotoxicity and fetotoxicity. Neurotoxicol Teratol 12 585-589. 

For example, some compounds will dissolve in water and others in fat (called a lipid). One of their 20 questions was, "Does the poisoning agent dissolve in water or fat To get an answer, they shook one mussel sample with a mixture of water and another mussel sample with a mixture of fat and injected the water and fat parts into different mice.The part of the mussel that dissolved in the water still caused the mice to scratch themselves, but the part that dissolved in fat didn t. So they knew they were looking for a chemical that dissolves in water. They divided the mussel over and over using many different methods, including chromatography, which is similar to the project at the end of this chapter. Finally, after four days of continuous work, the scientists had separated out of the mixture a pure substance that was the toxic compound.They compared all of its properties to compounds they already knew about and found a match a neurotoxic compound called "domoic acid. ... 

Other examples are carcinogenicity studies on complex mixtures (petroleum middle distillates, foundry fumes, pesticides, heterocyclic amines, diesel exhaust, and solid particles) neurotoxicity studies of mixtures of solvents alone or in combination with exposure to physical factors and toxicity stndies of outdoor air pollutants, focusing... 

Otto, D.A., Molhave, L., Goldstein, G., O Neil,)., House, D., Rose, G., Bemtsen, W., Counts, W., Fowler, S. and Hudnell, H.K. (1990a) Neurotoxic effects of controlled exposure to a complex mixture of volatile organic compounds. EPA Research and development, EPA/... 

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

When exposed to mixtures, chemicals in the exposure medium may affect each other s uptake by humans in a manner that is analogous to some of the bioavailability effects outlined here for environmental species. This was, for instance, shown for the neurotoxicity of EPN (O-ethyl-O-4-nitrophenyl phenylphosphono-thionate), which was enhanced by aliphatic hydrocarbons due in part to increased dermal absorption (Abou-Donia et al. 1985). It was also shown that dietary zinc inhibits some aspects of lead toxicity, which could in part be explained by decreasing dietary lead absorption (Cerklewski and Forbes 1976). Other examples of interactions of chemicals at the uptake phase in humans, which may in part be related to bioavailability interactions, are summarized in Table 1.3. 

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