Thresholds high-dose studies

The current health risks associated with exposure to low-dose radiation are extrapolated from high-dose data taken from the Life Span Study of the Japanese atomic bomb survivors. Currently, a linear no threshold extrapolation is recommended. The numerous technical reports and scientific papers about the Japanese A-bomb survivors were widely interpreted as showing that the effects of occupational exposures to radiation would be too small to detect in epidemiological studies. However, questions about the reliability of the A-bomb results were presented by Stewart and Kneale [2]. Their Oxford Childhood Study observed that children whose in utero exposures were as little as 10 to 20 mSv had 40% more childhood leukemias than those who were not exposed. No similar effects are reported in the A-bomb data. Of course, the finding of no effect is not a compelling argument for or against a safe dose. 

In traditional toxicological methods of determining virtually safe doses of hazardous chemicals, nominal thresholds for deterministic responses in humans are estimated based on a NOAEL obtained in human or animal studies. In most high-quality studies, NOAEL is approximately the same as the lower confidence limit of the benchmark dose that corresponds to a 10 percent increase in the number of responses. Thus, as an alternative to the benchmark dose method, the nominal threshold in humans could be set at a factor of 10 or 100 lower than NOAEL obtained in a high-quality human or animal study. However, the benchmark dose method preferred by NCRP... 

In particular, high-dose data usually cannot identify a threshold. A threshold is a dose or exposure below which there is no effect. It is often assumed that there is no threshold for an end point, like a gene mutation, that may involve one molecule of the toxicant and one target molecule in such a case, the dose-response relationship would be linear at low doses. If the observed relationship is linear over the dose range studied and if the fitted line is extrapolated to no effect (or the background frequency of effects) at zero dose, linear kinetics with no threshold are likely. But data are usually not clear. Even such a large carcinogenesis study as the EDqi study conducted by... 

The approach taken by this Committee is that, unless there is evidence to the contrary, it will be assumed that there is no threshold. If it is necessary to extrapolate from high-dose data, the best procedure is to interpolate linearly between the effect at zero dose and the lowest reliable data point(s). The lower the doses studied, the more reliable is this interpolation. 

The effects of genotoxic compounds are considered non-threshold. Thus, risk assessment for a given exposure is usually performed by a linear or sub-linear extrapolation from the high dose effects observed in animals to the lower human exposure. Since the outcome of the extrapolation depends on the model applied and extrapolation over different orders of magnitude is error prone, the European Food and Safety Authority (EFSA 2005) recommended to avoid this extrapolation and proposed the MOE approach. This approach uses the benchmark dose, or the T25 calculated from a carcinogenicity study and compares this with human exposure. A MOE of 10,000 and more is considered to be of minor concern. The advantage is that neither a debatable extrapolation from high to low doses needs to be performed nor are hypothetical cancer cases calculated. For details of the different approaches see, SCHER, SCCP, SCENIHR (2008). 

Animal studies show the olfactory and limbic pathways are particularly susceptible to kindling, the ability of a stimulus previously unable to induce a seizure to later induce one. Animal studies also show that acute administration of a high dose or intermittent repeated low-dose exposures to chemicals cause limbic kindling , and that this response is amplified depending on the time between stimuli. Kindling without a seizure has been shown to cause affective behavior changes in animals. Kindling could amplify reactivity and lower the threshold response to low levels of chemicals. 

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