Traditional Toxicology

If we consider both the specific immunotoxicity assays surveyed earlier in this chapter and the arrays of endpoints evaluated in traditional toxicology studies, which may be indicative of an immune system effect, these guidelines leave many potential questions unanswered. As additional data on individual endpoints indicative of... 

In some instances additional specialized studies may be required to assess drug-specific toxicological concerns. For example, hypersensitivity tests may be required for the -lactam antibiotics FDA has recently been concerned with how this standard human food safety assessment process accurately determines the safe concentration of antibiotic residues based on the traditional toxicological end-points. Of particular concern was the impact of low levels of antibiotics on the intestinal microflora. 

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... 

Safety factor approach for chemicals that cause deterministic effects. Traditional toxicologic procedures for chemicals that can induce deterministic effects, which are assumed to have a threshold dose, define RfD for humans or animals as some fraction of NOAEL. This fraction is determined by establishing safety factors to account for weaknesses and uncertainties in the data and in the extrapolation from animals to humans. In the safety factor approach, doses below RfD are assumed not to result in a response because they are below the threshold of toxicity (Dourson and Stara, 1983 Renwick and Lazarus, 1998 Weil, 1972). 

Animal Data. The second assumption states that the traditional toxicological tests involving rats and mice consistently reflect human response to chemicals. 

In addition. Section 512 of the Act has been interpreted to include the need to confirm that the level of antimicrobial residues present in food have no clinically relevant effect on the human intestinal microflora. Accordingly, for antimicrobial compounds, antimicrobial-specific issues are considered along with traditional toxicological studies and additional testing may be necessary. CVM has recently published a guidance document that serves as an initial step in... 

Traditional toxicology addresses the toxic effects of single chemicals and even some mixtures (additivity, potentiation, and synergism) well, but it is unable to account for some observed effects of chemical mixtures. These unexplained effects often ensue when exposures are to mixtures of lipophilic and hydrophilic chemicals. Octanokwater partition coefficients serve to predict the lipophilic or hydrophilic nature of chemical compounds. 

Optimized preclinical development can be a tremendous aid to the design of early clinical studies. This optimization will include a thorough study of preclinical safety by combining traditional toxicology studies with novel methods in toxicopro-teomics, toxicogenomics, and metabolomics. These new -omics will lead to novel biomarkers to predict toxicology and efficacy. 

Although the Procedure for the Safety Evaluation of Flavoring Agents does not require toxicological data in every instance, but rather relies primarily on structure-activity relationships to assess safety, this study confirmed that on the basis of a more traditional toxicological process of evaluating chemical safety, the procedure showed that the evaluated substances did not present a concern for safety at current estimates of intake. ... 

These issues are subject to considerable disagreement. Certainly argument (1) is weak at best—while traditional toxicology studies do not include a group dosed at the projected clinical dose, the lowest dose is usually at a modest multiple of such a dose (5 or 10 times) within the range of doses desirable to be covered in a safety pharmacology study. 

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