Scientific and Regulatory Policy Committee: Recommended ("Best") Practices for Determining, Communicating, and Using Adverse Effect Data from Nonclinical Studies.

Recommendations (best practices) are provided by the Society of Toxicologic Pathology's Adversity Working Group for making consistent interpretations of test article-related effects as "adverse" and assigning a "no observed adverse effect level" (NOAEL) in nonclinical toxicity studies. Adverse is a term indicating "harm" to the test animal, while nonadverse indicates lack of harm. Adverse findings in the study reports should be defined in relation to effects on the test species used and within the context of the given study. Test article-related effects should be described on their own merits, and decisions to consider them as adverse or nonadverse should be justified. Related effects may be discussed together; in particular, markers of toxicity that are not in and of themselves adverse ideally should be discussed in conjunction with the causal toxicity to determine adversity. Adverse findings should be identified in subreports (clinical data, pathology data, etc.) if sufficient information is available, and/or in the final study report as individual or grouped findings, but study NOAELs should be established at the level of the overall study report. Interpretations such as "not biologically relevant" or "not toxicologically important" should be avoided unless defined and supported by scientific rationale. Decisions defining adverse findings and the NOAEL in final study reports should combine the expertise of all contributing scientific disciplines. Where possible, use of NOAELs in data tables should be linked to explanatory text that places them in context. Ideally, in nonclinical summary documents, NOAELs from multiple studies are considered together in defining the most important adverse responses in the most sensitive species. These responses are then considered along with an understanding of their likely mechanisms, as well as other information such as variability in species sensitivity, comparative pathology, reversibility and progression, kinetics, and metabolism of the test substance to help assess human risk.

Hepatic drug-metabolizing enzyme induction and implications for preclinical and clinical risk assessment.

Hepatic drug metabolizing enzyme (DME) induction complicates the development of new drugs owing to altered efficacy of concomitant treatments, reduction in exposure resulting from autoinduction, and potential generation of toxic metabolites. Risk assessment of DME induction during clinical evaluation is confounded by several uncertainties pertaining to hazard identification and dose response analysis. Hepatic DME induction rarely leads to clinical evidence of altered metabolism and toxicity in the patient, which typically occur only if the DME induction is relatively severe. High drug doses are associated with a greater likelihood of hepatic DME induction and downstream effects; therefore, drugs of low potency requiring higher dosing tend to lead to a greater risk of drug-drug interactions. Vigilance in clinical trials for increased or diminished drug effect and, specifically, pharmacokinetic studies in the presence of other drugs and concomitant diseases are necessary for a drug risk assessment profile. Efforts to remove hepatic DME-inducing drugs from development can be facilitated with current in vitro and in vivo assessments and will improve with the development of newer technologies. A carefully tailored case-by-case approach will lead to the development of efficacious drugs with an acceptable risk/benefit profile available to patients.

Evaluation of the erythroid regenerative response in two different models of experimentally induced iron deficiency anemia.

Anemia was induced in weanling Sprague Dawley rats either by feeding an iron-deficient diet or by chronic phlebotomy. The erythroid regenerative response was then evaluated before and after a hemolytic event, and results were compared with those of a third group of control nonphlebotomized rats fed an iron-replete diet. Diet and phlebotomy groups developed a similar degree of anemia (mean hemoglobin concentration 7.9 g/dL and 7.8 g/dL, respectively; controls, 13.9 g/dL) and hypoferremia (mean serum iron concentration 25.4 microgram/dL and 34.9 microgram/dL, respectively; controls, 222.0 microgram/dL). However, the anemia in diet rats was nonregenerative (reticulocyte count, 83.1 X 10(3) cells/microliter) and associated with bone marrow erythroid hypoplasia; whereas the anemia in phlebotomy rats was regenerative (reticulocyte count, 169.6 X 10(3) cells/microliter) and associated with bone marrow erythroid hyperplasia. Thrombocytosis was seen in diet rats (1,580 X 10(3) cells/microliter) but not phlebotomy rats (901 X 10(3) cells/microliter) when compared with controls (809 X 10(3) cells/microliter). To further evaluate the regenerative capability, phenylhydrazine (PHZ) was administered to induce hemolysis. Erythrocyte mass declined approximately 25% in all groups, including controls. The reticulocytosis (265.3 X 10(3) cells/microliter) seen in phlebotomy rats was earlier and significantly greater than that seen in either diet or control rats. Hemoglobin concentration returned to pre-PHZ concentrations (7.9 g/dL) in phlebotomy rats within 4 days posthemolysis. In diet rats, the maximal regenerative response (176.3 X 10(3) cells/microliter) was not seen until 8 days posthemolysis, and hemoglobin (7.5 g/dL) did not return to pre-PHZ concentrations during the 8-day study. In many aspects, the anemia seen following diet- or phlebotomy-induced iron deficiency was similar. However, the erythroid regenerative capability varied depending on the mechanism by which anemia was induced and furthermore altered the efficiency of hemoglobin production following a hemolytic event. These results suggest that the availability of iron in the diet may modulate the pathogenesis of iron deficiency anemia.