Opinion ID: 510618
Heading Depth: 3
Heading Rank: 2

Heading: Choice of physiological signs to indicate the MTD

Text: 22 Petitioners also assert that the FDA arbitrarily departed from accepted standards by accepting changes in spleen and liver weights and depression of blood glucose levels in the second generation adult rats as evidence that two percent was the correct MTD. Petitioners contend that weight loss, enzyme level shift, and shortened lifespan are the exclusive criteria for determining the MTD. They cite the Red Book statements that the MTD should not reduce longevity and that signs of toxicity may be indicated by changes in serum enzyme levels or slight depression of body weight gain (less than 10 percent). Red Book at 58, J.A. at 84 (emphasis added). 23 The FDA's assertion in its decision that the MTD may be based on effects other than those mentioned in the Red Book is supported by permissive language in the manual coupled with considerable evidence from other sources. We note at the outset that record evidence reveals significant uncertainty in the scientific community with respect to the best method of selecting the MTD. See Office of Science and Technology Policy, Chemical Carcinogens: A Review of the Science and Its Associated Principles (OSTP Draft Report), 49 Fed.Reg. 21,594, 21,633 (May 22, 1984), J.A. at 118 (The question of what maximum dose should be administered may be the most controversial issue concerning bioassays.); see also OSTP Final Report, 50 Fed.Reg. 10,372, 10,413 (Mar. 14, 1985) (same). A number of the scientific experts testifying at the hearing discussed the difficulties with the MTD as a toxicologic concept and the lack of consensus as to the precise criteria--both quantitative and qualitative--for determination of the MTD. 24 With respect to specific criteria used to assess the MTD, Dr. John Doull, a toxicologist on the Board of Scientific Counselors of the National Toxicology Program, stated that relevant effects could include any adverse phenomenon which is detrimental to the health and survival of the exposed population. The OSTP Final Report reiterates that a range of biological effects may be considered: 25 [While t]he MTD was initially based on a weight gain decrement observed in the subchronic study    [m]ore recent studies    indicate refinement of MTD selection on the basis of a broader range of biological information. Alterations in body and organ weight and clinically significant changes in hematologic, urinary and clinical chemistry measurements may be useful in conjunction with the usually more definitive toxic, gross, or histopathologic endpoints. 26 OSTP Final Report, 50 Fed.Reg. at 10,413. On the basis of this statement, published after the promulgation of the Red Book, the FDA was entitled to reject as outmoded exclusive reliance on criteria listed in the FDA manual. The three expert witnesses testifying for petitioners cited no other authority for their assertions that increased mortality and reduction in weight gain were the definitive measures of the MTD. The FDA plainly chose to discount these experts' opinions as superseded by more recent evidence. It is the prerogative of the FDA to weigh and evaluate this conflicting testimony, and the record indicates that the FDA's conclusions were reasonable. Thus, the FDA's determination that organ weight and blood glucose effects were valid signs of the MTD is supported by a fair evaluation of the record as a whole.