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.

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.

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.

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.

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.

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.

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.

Analysis of thresholds for carcinogenicity.

Re-evaluations of large prominent studies, e.g. the ED01 study and N-nitrosodiethylamine, unequivocally have demonstrated that thresholds exist for carcinogenicity when the dose-response curves for animal studies done at high doses are calculated according to fundamental principles of chemistry.

Correlation of tumors with DNA adducts from methyl eugenol and tamoxifen in rats.

Data on percent tumors in male rats after administration of methyl eugenol, obtained from the National Toxicology Program, or tamoxifen were plotted on a linear scale for percent tumors against the dose on a logarithmic scale. Data on (32)P-postlabelled DNA adducts were plotted on the same graphs for each of these two compounds in order to correlate adduct formation and tumor incidence with dose. The resulting graph for methyl eugenol showed a linear response for both adduct formation and tumor incidence.

Dose-response curves in chemical carcinogenesis.

Extrapolation from studies of chemical carcinogenicity in rodents, at high doses, to humans, at the typically low doses to which we are exposed, has been one of the most controversial issues in toxicology. Many chemical carcinogenesis experiments currently are evaluated on a linear scale for dose. Log dose has been the standard for decades in pharmacology and toxicology for noncancer toxicities and there is no reason to think that it should not apply to chemical carcinogenesis.

The FEMA GRAS assessment of cinnamyl derivatives used as flavor ingredients.

This publication is the seventh in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology.

Comparison of human exposures to selected chemicals with thresholds from NTP carcinogenicity studies in rodents.

The National Toxicology Program (NTP) Technical Reports online database was reviewed to find chemicals that were reported to show clear evidence of carcinogenicity in the NTP rodent studies and for which data on human exposure could be found. Six representative compounds were selected. Three volatile compounds: ethyl benzene, perchloroethylene, and methylene chloride; two drugs in current use: phenytoin and primidone; and one naturally occurring, widely used, flavor: allyl isothiocyanate, were selected.

Thresholds in chemical carcinogenesis: what are animal experiments telling us?

It appears that the controversy over whether animal experiments demonstrate a threshold for carcinogenicity from chemicals was due to an error in plotting dose response. A linear (arithmetic) scale for the dose of chemicals obscures effects at doses below those used in the experiment and distorts the effect seen over the range of doses used. Gaddum (Nature 156: 463, 1946) pointed out that, empirically, dose should be on a logarithmic scale to effect a linear quantal response.

Thresholds of carcinogenicity in the ED01 study.

The results of the articles on the carcinogenicity of 2-acetylaminofluorene (J. H. Farmer et al.

Thresholds of carcinogenicity of flavors.

Fifteen compounds approved by the FEMA (Flavor and Extract Manufacturers Association) expert panel as GRAS (Generally Recognized As Safe) and structurally related compounds have been reported to be carcinogenic in rodent studies. The dose response of the 15 compounds in these studies was scrutinized by attempting to plot the percentage of animals with tumors against the dose of the compound on a logarithmic scale in molecules of compound per kg per day (the Rozman scale). Four compounds had either no or an inverse dose response: benzaldehyde, furfural, 3,4-dihydroxycoumarin, and gamma-buterolactone.