History of dose response.

An abbreviated history of the dose-response curve or chemical concentration-effect relationship is presented in this article. No attempt has been made to include all references on the subject. Just an outline, overview, and discussion of the most important eras are presented. The history of dose response may be divided roughly into three Eras, Preclassical, Classical, and Current. Paracelsus, who lived from 1493 to 1541, must be recognized as the first one to realize that dose was the most important issue to deal with in determining whether a chemical was toxic or not. However, that issue seems to have been forgotten and is still ignored by some. The Classical Era began about 1900 and ended about t; he time of the death of Gaddum in 1965, during which almost all of the progress had been made in solving the parameters to use in analyzing data. The Current Era began with the acceptance of the linearized multistage model in the mid-1970's. In this author's opinion, the biggest mistake in all of toxicology occurred with the acceptance and use of the linearized multistage for DNA-reactive carcinogens with dose on a linear scale. It had been clearly established in the Classical Era that dose should be plotted on a logarithmic scale. Plotting dose on a linear scale distorts the curve for low doses so that any attempt to detect the relationship of dose of carcinogen to carcinogenesis is impossible.

Commentary on ''Toxicity testing in the 21st century: a vision and a strategy''.

The report of the National Academy of Sciences entitled 'Toxicity Testing in the 21st Century: A Vision and a Strategy,' hereinafter referred to as 'The Report,' is more of a vision than of a strategy. The present article addresses three observations made on The Report; namely, dose response, PBPK modeling, and in vitro testing. An additional observation this author has of the document is that a role for a scientist who can analyze the big picture is missing from the document. Science today is necessarily composed of specialists in many areas because science today encompasses many diverse, specific fields. Each specialist is in a world of his or her own and unable to integrate all the facts. Must we wait for another Newton or Einstein?

Thermodynamic basis for expressing dose logarithmically.

The current explanations for using a logarithmic scale for the dose of a chemical, administered to a biological system, have all been empirical. There is a fundamental, thermodynamic reason why a logarithmic scale must be used. The chemical potential is the effect that a chemical exerts on any system, including biological systems. The chemical potential of a chemical in any system is directly proportional to the logarithm of its activity or concentration. Lack of understanding of this concept and the consequent use of a linear scale for dose has led to misinterpretation of many biological experiments.

Concordance of thresholds for carcinogenicity of N-nitrosodiethylamine.

Three publications on the carcinogenicity of N-nitrosodiethylamine (NDEA) in the livers of F-344 or Wistar rats were examined for concordance of the data. Two reports recorded the appearance of tumors after treatment with NDEA, although one used a different dosing schedule that included phenobarbital promotion. Two studied glutathione S-transferase-placental positive (GST-p+) foci in liver at several doses. One also analyzed DNA for adducts from NDEA. This analysis revealed that when the dose was calculated in molecules/kg/day, the thresholds for the incidence of liver tumors were different by about 1.5 orders of magnitude. But when the dose was calculated as the total cumulative dose, the thresholds for tumor appearance (about 10(20.3) molecules/kg) were in agreement within the error of calculation. Combining the data for GST-p+ foci revealed remarkable agreement between the two reports and a threshold for the appearance of these foci at about 10(19.5) molecules/kg of total cumulative dose of NDEA. DNA adducts fit an exponential curve better than a linear. GST-p+ foci and adducts from NDEA were observed at doses below the threshold dose for the appearance of tumors. These results suggest that: cumulative dose is a better metric than daily dose and that adducts and GST-p+ foci appear at doses below those at which tumors appear. These results further support the observations of the authors that thresholds for carcinogenicity of this genotoxic carcinogen exist and that adducts and altered foci appear at lower doses than the threshold for carcinogenicity.

Comparisons of thresholds for carcinogenicity on linear and logarithmic dosage scales.

Comparisons on a linear and the Rozman logarithmic scale for dosage versus carcinogenicity in rodents are presented for methyl eugenol (ME), nitrosodiethylamine (NDEA), ethyl carbamate (EC) and 2-acetylaminofluorene (AAF). Each of these chemicals has been shown to be carcinogenic in experimental animals and, in addition, humans are regularly exposed to at least three of these compounds (ME, NDEA, EC) in foods. Although the source of adducts from AAF is not known, the aminofluorene (AF) adduct is present in humans. Plotted on the same graphs are either some doses from common foods (ME, NDEA, EC) or adducts (AF) on human haemoglobin, for perspective, with their thresholds for carcinogenesis in animals. Use of a linear scale when comparing doses administered to animals in studies of carcinogenicity with doses of those same chemicals to which humans are exposed does not provide useful, comparative information. On the other hand, the Rozman logarithmic scale for dose allows one to put these relative doses in perspective. It is also evident that forcing a linear extrapolation through the zero, zero origin does not agree with the experimental data. Further analyses for goodness of fit for these dose responses reveal that the dose response for three of these compounds (ME, NDEA, EC) appears to be linear with the logarithm of the dose. However, AAF appears to be linear with the logarithm of the dose for bladder, but not for liver. It is suggested that the high background incidence of tumours in the BALB/c StCrlfC3Hf/Nctr mouse liver may confound the interpretation of dose response from AAF carcinogenesis in mouse liver.

Criteria for the safety evaluation of flavoring substances. The Expert Panel of the Flavor and Extract Manufacturers Association.

The current status of the GRAS evaluation program of flavoring substances operated by the Expert Panel of FEMA is discussed. The Panel maintains a rigorous rotating 10-year program of continuous review of scientific data related to the safety evaluation of flavoring substances. The Panel concluded a comprehensive review of the GRAS (GRASa) status of flavors in 1985 and began a second comprehensive review of the same substances and any recently GRAS materials in 1994. This second re-evaluation program of chemical groups of flavor ingredients, recognized as the GRAS reaffirmation (GRASr) program, is scheduled to be completed in 2005. The evaluation criteria used by the Panel during the GRASr program reflects the significant impact of advances in biochemistry, molecular biology and toxicology that have allowed for a more complete understanding of the molecular events associated with toxicity. The interpretation of novel data on the relationship of dose to metabolic fate, formation of protein and DNA adducts, enzyme induction, and the cascade of cellular events leading to toxicity provides a more comprehensive basis upon which to evaluate the safety of the intake of flavor ingredients under conditions of intended use. The interpretation of genotoxicity data is evaluated in the context of other data such as in vivo animal metabolism and lifetime animal feeding studies that are more closely related to actual human experience. Data are not viewed in isolation, but comprise one component that is factored into the Panel's overall safety assessment. The convergence of different methodologies that assess intake of flavoring substances provides a greater degree of confidence in the estimated intake of flavor ingredients. When these intakes are compared to dose levels that in some cases result in related chemical and biological effects and the subsequent toxicity, it is clear that exposure to these substances through flavor use presents no significant human health risk.

Human exposures to acrylamide are below the threshold for carcinogenesis.

Dose-response calculations for a threshold of carcinogenesis in animal studies do not support the notion that acrylamide (ACR) with the present status of consumption in food is carcinogenic for humans. This is in agreement with the recent reassuring epidemiological studies which have shown a lack of correlation between exposure to ACR in food and the incidence of cancer.