Low-dose exposure

A recent method, still in development, for determining total 4-nitrophenol in the urine of persons exposed to methyl parathion is based on solid phase microextraction (SPME) and GC/MS previously, the method has been used in the analysis of food and environmental samples (Guidotti et al. 1999). The method uses a solid phase microextraction fiber, is inserted into the urine sample that has been hydrolyzed with HCl at 50° C prior to mixing with distilled water and NaCl and then stirred (1,000 rpm). The fiber is left in the liquid for 30 minutes until a partitioning equilibrium is achieved, and then placed into the GC injector port to desorb. The method shows promise for use in determining exposures at low doses, as it is very sensitive. There is a need for additional development of this method, as the measurement of acetylcholinesterase, the enzyme inhibited by exposure to organophosphates such as methyl parathion, is not an effective indicator of low-dose exposures. 

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

Reape JM. 1982. Neurologic health impact on workers with chronic low dose exposure to aryl phosphates. Thesis submitted to the faculty of the graduate school of the university of Minnesota. 

Evaluate the influence of body stores of Nat Inst of Diabetes And lead and chronic low dose exposure to Digestive And Kidney lead from the environment Diseases... 

Dichlorobenzene distributes to fatty tissues and is probably retained there at low concentrations (EPA 1986d Hawkins et al. 1980 Morita and Ohi 1975 Morita et al. 1975). However, most of an absorbed dose is excreted within 5 days of exposure (Hawkins et al. 1980), and there is no evidence suggesting that the low levels of 1,4-dichlorobenzene that are likely to remain in fatty tissues would cause adverse effects. For these reasons, methods for enhancing elimination of 1,4-dichlorobenzene shortly after high-dose exposure could reduce toxic effects however, no such methods have been identified. Methods that could enhance the elimination of 1,4-dichlorobenzene after high- or low-dose exposure in humans or laboratory animals have not been reported. 

This model assumes that any dosage effect has the same mechanism as that which causes the background incidence. Low-dose linearity follows directly from this additive assumption, provided that any fraction of the background effect is additive no matter how small. A best fit curve is fitted to the data obtained from a long-term rodent cancer bioassay using computer programs. The estimates of the parameters in the polynomial are called Maximum Likelihood Estimates (MLE), based upon the statistical procedure used for fitting the curve, and can be considered as best fit estimates. Provided the fit of the model is satisfactory, the estimates of these parameters are used to extrapolate to low-dose exposures. 

Interactions between chemicals administered to humans at high doses have been known for many years in the field of pharmacology. However, these experiences are not directly useful for predicting toxic effects of mixtures of environmental chemicals because the exposure levels for the general human population are relatively low and interactions occurring at high doses may not be representative for low-dose exposures (Konemann and Pieters 1996). 

Wada et al. extended Yamada s observations on the same men,7 finding 33 deaths from respiratory tract cancers for 1952-1967, compared with an expected 0.9, a relative risk of nearly 37. For 960 employees not exposed to H, Wada et al. found only three deaths from respiratory tract cancer, compared with 1.8 expected. These data point to a connection between long, low-dose exposure to H and later cancer, especially in the respiratory tract. 

Although DM has greater acute toxicity to the respiratory tract than CS and CN, Edgewood subjects appeared to recover shortly after exposure. Given the available information on DM and the short low-dose exposures, It Is Impossible to predict whether Edgewood subjects exposed to DM will suffer any longterm effects of the exposure. 

Although they are not extensive, the data of Punte et al.l 2 suggest that nonanoyl morpholide Is less toxic than CN or DM. Nonanoyl morpholide appears more irritating than CN or DM, but may have less persistent effects. No definitive Information is available on the possibility of long-term effects of exposure to nonanoyl morpho-llde. However, given the available information on nonanoyl morpholide and the short-term low-dose exposures of Edgewood subjects to It, the Committee believes that long-term health effects on the subjects are unlikely. 

Given the available Information on subjects exposed to 118539, 123175, 126312, CS36579, and EA 2366 and their short, low-dose exposures, one cannot predict long-term health effects of these agentL. The discomfort associated with the exposures was marked, but exposures were short and recovery appeared complete. 

Beyer, A., Wang, K., Umble, A.N., Wolt, J.D., and Cunnick, J.E. (2007). Low-dose exposure and immunogenicity of transgenic maize expressing the Escherichia coli heat-labile toxin B subunit. Environ. Health Perspect. 115(3) 354-360. 

Land, C.E., Boice, J.D., Jr., Shore, R.E., Norman, J.E., and Tokunaga. M. (1980). Breast cancer risk from low-dose exposures to ionizing radiation Results of parallel analysis of three exposed populations of women, J. Natl. Cancer Inst. 65, 353. 

Overall, our analyses have shown that HERP values for some historically high exposures in the workplace—to butadiene and tetrachloroethylene—and to some pharmaceuticals—clolibrate —rank high, and that there is an enormous background of naturally occurring rodent carcinogens in typical portions of common foods. The background of natural exposures casts doubt on the relative importance of low-dose exposures to residues of synthetic chemicals such as pesticides. (A committee of the National Research Council of the National Academy of Sciences reached similar conclusions about natural vs. synthetic chemicals in the diet, and called for further research on natural chemicals.) 16... 

The acute and/or chronic nature of the toxicity of a chemical should be part of any decision-making process about its use or subsequent release. The focus cannot be solely on reduction of acute hazards, which tends to be easily achievable. The majority of cases in which chemicals have been released into the environment, only to cause serious ecological impacts over large spatial scales, were usually identified after many years, and at chronic low-dose exposures, with low acute toxicity to nontarget organisms. The classic examples of DDT and other chlorinated pesticides such as dieldrin and toxaphene, along with PCBs, exemplify the flaws in an approach that focuses on acute hazards, with more recent examples being the perfluorinated... 

From this discussion, it is clear that the reversible and irreversible interactions may give rise to different types of response. With reversible interactions, it is clear that at low concentrations, occupancy of receptors may be negligible with no apparent response, and there may, therefore, be a threshold below which there is a "no-effect level." The response may also be very short, as it depends on the concentration at the site of action, which may only be transient. Also, repeated or continuous low-dose exposure will have no measurable effect. 

Numerous mathematical models have been developed in attempts to estimate potential risks to humans from low-dose exposures to carcinogens. Each model incorporates numerous unverifiable assumptions. Low-dose calculations are highly model dependent, widely differing results are commonly obtained, and none of the models can be firmly justified on either statistical or biological grounds (22). Thus, the decision to use this approach and the choice of how to do the calculations are matters of judgment. Among the choices that the decision makers must consider are which model(s) to employ, which assumptions to incorporate, and which acceptable risk to allow. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

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