Related Experiment Videos
Anticarcinogenic responses in rodent cancer bioassays are not explained by random effects
1Department of Physics, Jefferson Laboratories, Harvard University, Cambridge, Massachusetts 02138, USA.
Abstract:
Anticarcinogenicity in a long-term rodent bioassay is defined as a statistically significant decrease of a specific tumor type in a dosed group following chemical exposure. About 92% of chemicals tested by the National Toxicology Program prior to 1983 reveal at least one site with a significant (p < or = 0.05) tumor rate decrease in one or more tested groups, a result consistent with those of J. K. Haseman and F. M. Johnson (1996, Mutat. Res. 350, 131-141) for a database of recently tested chemicals. Detection of tumor decreases in a specific site can be explained not only by biological effects, but also as a result of random variability in the background tumor rates, decreases in body weight, or decreases in survival of treated animals. This paper evaluates the rate of false-positive anticarcinogenic findings due to random effects (variations in tumor rates and the multiple comparisons undertaken in evaluating a bioassay), while a companion paper addresses the influence of weight and survival depression. Monte-Carlo simulation was conducted to assess the contribution of random effects. This contribution was found to be important even when a statistical significance cutoff of p0 < or = 0.05 was chosen. If a more stringent statistical criterion was used (p0 < or = 0.01 or p < or = 0.005), the proportion of false positive determinations diminishes. The number of anticarcinogens in the database remains substantially higher than predicted by the stimulations. An examination of the distribution of all p values (T. Schweder and E. Spjøtvoll, 1982, Biometrika 69, 493-502) also indicates that statistically significant anticarcinogenic responses are found in the database at a higher rate than would result from purely random responses. Finally, the cross-species prediction of anticarcinogenic responses was examined in a manner similar to a study of cross-species prediction of carcinogenic responses (G. M. Gray et al., 1995, Reg. Toxicol. Pharmacol. 20, 281-301). The analyses show that anticarcinogenic effects in one rodent species predict well anticarcinogenic effect in another rodent species. It seems likely that biological factors are involved in anticarcinogenic responses observed in rodent cancer bioassays.
Insights
This study reveals that many anticarcinogenic findings in rodent bioassays may be false positives due to random variation. However, biological factors likely contribute to true anticarcinogenic responses, which are predictable across species.
Area of Science:
- Toxicology
- Carcinogenesis and Chemoprevention
- Statistical Modeling in Biological Assays
Background:
- Anticarcinogenicity in rodent bioassays is defined as a statistically significant decrease in tumor type following chemical exposure.
- A high percentage of chemicals tested by the National Toxicology Program show decreased tumor rates, consistent with previous findings.
- Tumor rate decreases can result from biological effects or random variability, decreased body weight, or reduced survival.
Purpose of the Study:
- To evaluate the rate of false-positive anticarcinogenic findings attributed to random effects, such as tumor rate variations and multiple comparisons.
- To assess the impact of statistical significance cutoffs on false-positive determinations.
- To examine the cross-species predictability of anticarcinogenic responses.
Main Methods:
- Monte Carlo simulations were used to assess the contribution of random effects to false-positive anticarcinogenic findings.
- Statistical significance levels (p < or = 0.05, p < or = 0.01, p < or = 0.005) were analyzed.
- P-value distributions were examined, and cross-species prediction of anticarcinogenic responses was evaluated.
Main Results:
- Random effects were found to be a significant contributor to false-positive anticarcinogenic findings, even at a p < or = 0.05 significance level.
- Using more stringent statistical criteria (p < or = 0.01 or p < or = 0.005) reduced the proportion of false positives.
- The observed number of anticarcinogens exceeded predictions from simulations, and statistically significant anticarcinogenic responses occurred more frequently than expected by chance.
- Anticarcinogenic effects demonstrated good predictability between different rodent species.
Conclusions:
- While random variability contributes to false positives, biological factors are likely involved in true anticarcinogenic responses observed in rodent bioassays.
- Anticarcinogenic effects identified in one rodent species are generally predictive of effects in another.
- The findings highlight the importance of rigorous statistical evaluation in interpreting rodent bioassay results for anticarcinogenicity.