Limitations of probit plots in pharmacogenetics: requirement of genetic analyses to test hypotheses based on graphical methods.
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Antipyrine↗
Biomedical subjects
D W Gaylor
Publications and source records attributed to D W Gaylor.
Spontaneous renal tubular carcinoma in Fischer-344 rat littermates.
Two of 632 Fischer-344 rats in a food restriction study had spontaneous, bilateral, multicentric renal tubular cell carcinomas. Although there were 104 litters represented in this study, both rats that developed this rare neoplasm were from the same litter. The littermates, one male and one female, were in the food-restricted treatment groups (60% of ad libitum intake) and were 550 and 447 days old, respectively, at death. The probability that the two rare bilateral renal neoplasms occurred by a chance event in littermates is approximately 0.8%. The apparent familial predisposition for development of specific types of neoplasms emphasizes the importance of randomization of individuals into treatment groups and consideration of lineage for rare tumors.
Animals↗
Study of sodium saccharin co-carcinogenicity in the rat.
A co-carcinogenicity experiment was conducted with female Sprague-Dawley rats in which the effects of short-term sodium saccharin dosing and initiation with a direct-acting carcinogen were examined in the urinary bladder. All initiated animals were administered 0.5 mg N-methyl-N-nitrosourea (MNU) by instillation into the bladder at 8 wk of age. The animals were also given saccharin at one of four levels in the diet (0, 1.0, 2.5 or 5%) for 4 wk either (1) just before treatment with MNU (4-8 wk of age), (2) centred on treatment with MNU (6-10 wk of age) or (3) after MNU treatment (8-12 wk of age). Additionally, a group of animals was exposed to saccharin through the milk for 3 wk by dosing the mothers, starting on the day of parturition. The animals were held on control diet until interim killing of 20 animals per group at about 590 days of age, removal for morbidity, or terminal killing of the remainder of 60 animals per treatment around 780 days of age. A histopathological examination was made of the urinary tract and the relationship of saccharin dose to bladder tumour prevalence analysed statistically. A consistent increase (with very weak statistical significance) in tumour rate at interim killing, and for the pathology data overall, was shown by the 2.5% dose group given saccharin from 8 to 12 wk of age. Tumour prevalences of 47.6 and 40.7% v. control prevalences of 21.1 and 25.4% were observed for the two time periods (P values < 0.076 and < 0.0853, respectively). All groups given saccharin neonatally showed increased tumour prevalence for both time periods, but none of the differences was statistically significant at the 95% confidence level. No consistent increase in tumour prevalence was seen in the groups given saccharin from 4 to 8 or 6 to 10 wk of age; thus, these data suggest that saccharin does not act as a strong co-carcinogen in the MNU-treated rat bladder.
Animals↗
Modeling for risk assessment of neurotoxic effects.
The regulation of noncancer toxicants, including neurotoxicants, has usually been based upon a reference dose (allowable daily intake). A reference dose is obtained by dividing a no-observed-effect level by uncertainty (safety) factors to account for intraspecies and interspecies sensitivities to a chemical. It is assumed that the risk at the reference dose is negligible, but no attempt generally is made to estimate the risk at the reference dose. A procedure is outlined that provides estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect and the dose of a chemical. Knowledge of biological mechanisms and/or pharmacokinetics can assist in the choice of plausible mathematical models. The mathematical model provides estimates of average responses as a function of dose. Secondly, estimates of risk require selection of a distribution of individual responses about the average response given by the mathematical model. In the case of a normal or lognormal distribution, only an estimate of the standard deviation is needed. The third step is to define an adverse level for a response so that the probability (risk) of exceeding that level can be estimated as a function of dose. Because a firm response level often cannot be established at which adverse biological effects occur, it may be necessary to at least establish an abnormal response level that only a small proportion of individuals would exceed in an unexposed group. That is, if a normal range of responses can be established, then the probability (risk) of abnormal responses can be estimated.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Methylenedioxyamphetamine↗
Point estimates of cancer risk at low doses.
There has been considerable discussion regarding the conservativeness of low-dose cancer risk estimates based upon linear extrapolation from upper confidence limits. Various groups have expressed a need for best (point) estimates of cancer risk in order to improve risk/benefit decisions. Point estimates of carcinogenic potency obtained from maximum likelihood estimates of low-dose slope may be highly unstable, being sensitive both to the choice of the dose-response model and possibly to minimal perturbations of the data. For carcinogens that augment background carcinogenic processes and/or for mutagenic carcinogens, at low doses the tumor incidence versus target tissue dose is expected to be linear. Pharmacokinetic data may be needed to identify and adjust for exposure-dose nonlinearities. Based on the assumption that the dose response is linear over low doses, a stable point estimate for low-dose cancer risk is proposed. Since various models give similar estimates of risk down to levels of 1%, a stable estimate of the low-dose cancer slope is provided by ŝ = 0.01/ED01, where ED01 is the dose corresponding to an excess cancer risk of 1%. Thus, low-dose estimates of cancer risk are obtained by, risk = ŝ x dose. The proposed procedure is similar to one which has been utilized in the past by the Center for Food Safety and Applied Nutrition, Food and Drug Administration. The upper confidence limit, s., corresponding to this point estimate of low-dose slope is similar to the upper limit, q1., obtained from the generalized multistage model. The advantage of the proposed procedure is that ŝ provides stable estimates of low-dose carcinogenic potency, which are not unduly influenced by small perturbations of the tumor incidence rates, unlike q1.
Humans↗
Dose-response models for developmental malformations.
An empirical dose-response model can generally be found for bioassay data, which provides a mathematical relationship between the incidence of a developmental malformation and dose of a toxicant in the experimental dose range. If biological principles and data can be used in the formulation of the dose-response model, the estimation of the incidence of malformations outside of the experimental dose range may be improved. In this paper, exponential growth of morphological structures in rodents during gestation is assumed. Further, it is assumed that some structural malformations are the result of reduced or delayed growth and the incidence of structurally normal fetuses is proportional to fetal weight raised to a power. When the exponential growth rate constant is reduced by dose raised to a power, a Weibull dose-response function is obtained. When the exponential growth rate constant is modeled by a polynomial function of dose, a polynomial-exponential dose-response model is obtained. The Weibull and the polynomial-exponential model, restricted to degrees from one up to the number of dosed groups, were fit to a database of bioassay data assembled from Teratology Vol. 1 (1968) to Vol. 42 (1990). In general the two models gave similar results and often gave exactly the same fit. The linear term appeared in the polynomial-exponential model in about one-fourth of the cases and was not related to the background incidence.
Abnormalities, Drug-Induced↗
An overview of the report: correlation between carcinogenic potency and the maximum tolerated dose: implications for risk assessment.
Current practice in carcinogen bioassay calls for exposure of experimental animals at doses up to and including the maximum tolerated dose (MTD). Such studies have been used to compute measures of carcinogenic potency such as the TD50 as well as unit risk factors such as q1 * for predicting low-dose risks. Recent studies have indicated that these measures of carcinogenic potency are highly correlated with the MTD. Carcinogenic potency has also been shown to be correlated with indicators of mutagenicity and toxicity. Correlation of the MTDs for rats and mice implies a corresponding correlation in TD50 values for these two species. The implications of these results for cancer risk assessment are examined in light of the large variation in potency among chemicals known to induce tumors in rodents.
Animals↗
Uncertainty in cancer risk estimates.
Several existing databases compiled by Gold et al. for carcinogenesis bioassays are examined to obtain estimates of the reproducibility of cancer rates across experiments, strains, and rodent species. A measure of carcinogenic potency is given by the TD50 (daily dose that causes a tumor type in 50% of the exposed animals that otherwise would not develop the tumor in a standard lifetime). The lognormal distribution can be used to model the uncertainty of the estimates of potency (TD50) and the ratio of TD50's between two species. For near-replicate bioassays, approximately 95% of the TD50's are estimated to be within a factor of 4 of the mean. Between strains, about 95% of the TD50's are estimated to be within a factor of 11 of their mean, and the pure genetic component of variability is accounted for by a factor of 6.8. Between rats and mice, about 95% of the TD50's are estimated to be within a factor of 32 of the mean, while between humans and experimental animals the factor is 110 for 20 chemicals reported by Allen et al. The common practice of basing cancer risk estimates on the most sensitive rodent species-strain-sex and using interspecies dose scaling based on body surface area appears to overestimate cancer rates for these 20 human carcinogens by about one order of magnitude on the average.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
International trends in the incidence of bone cancer are not related to drinking water fluoridation.
BACKGROUND: Because osteosarcomas may develop in rats exposed to fluoridated water, water fluoridation might pose a cancer risk to humans. METHODS: A time trend analysis of the cumulative risk (CR) of bone cancer for the period 1958-1987 for 40 cancer registry areas showed an increased risk for young males in Canada, Europe, and the United States, and a decreased lifetime risk for either sex in Europe. RESULTS: This was unrelated to water fluoridation and may have resulted from changes in coding practices. Bone cancer risk was inversely related to the incidence of cancers of unknown origin, suggesting that bone metastases were erroneously coded as primary bone cancer. In 1968-1972, most areas recorded more bone cancer deaths than new cases of the disease. CONCLUSIONS: The mortality/incidence ratio, but not the incidence rate (IR), has dropped sharply since then, which erodes the basis of past inferences relating cancer mortality to fluoridation.
Animals↗
Correlations of developmental end points observed after 2,4,5-trichlorophenoxyacetic acid exposure in mice.
A large-scale developmental toxicology study of 2,4,5-trichlorophenoxyacetic acid was conducted in four inbred strains and one outbred strain of mice. The most significant developmental effects observed were reduced fetal weight and increased incidences of cleft palate (malformation) and prenatal death (deaths/resorptions). The correlation coefficients among the proportion of deaths/resorptions, proportion of malformations, average fetal weights, and number of viable fetuses were investigated, with each variable measured on a per-litter basis. Generally, the correlation coefficients between average fetal weight and number of viable fetuses were negative for the control and low-dose groups in the C57BL/6, C3H/He, and BALB/c strains. Overall, the correlation coefficients between proportion of malformations and number of viable fetuses were not significant. The correlation coefficients between proportion of malformations and average fetal weight were negative for all but one case. The correlations were weak in the control and low-dose groups, in which the malformation rates were very low, and were strong in the high-dose groups. The correlation coefficients between proportion of deaths/resorptions and proportion of malformations were generally positive at the high doses; some negative correlations were observed in control and low-dose groups. The correlation coefficients between proportion of deaths/resorptions and average fetal weight were negative for the A/JAX and CD-1 strains. In summary, the strongest relationship observed was the negative correlation between fetal weight and malformation.
2,4,5-Trichlorophenoxyacetic Acid↗
Process of building biologically based dose-response models for developmental defects.
The problem of developing biologically-based dose-response models is addressed for predicting the prevalence of birth defects at low doses of toxic chemicals administered during pregnancy. To illustrate the process of incorporating biological information, a model is postulated to predict the prevalence of cleft palate for a chemical that reduces embryonic/fetal growth, which results in inadequate palatal cells for closure. Experimental bioassay data examining the prevalence of cleft palate in mice exposed to the herbicide 2,4,5-T are used to illustrate the process. With the limited data available, it is necessary to assume a model for cell growth and the relationship between the cell growth rate parameter and dose of 2,4,5-T. Also, a relationship between cleft palate prevalence and growth is assumed and then checked with experimental data. The purpose of the paper is not to provide a universal biologically based dose-response model for cleft palate, but rather to demonstrate the extent, and type of information and data required. It remains to be seen if the form of the model is appropriate for chemicals that primarily produce embryo/fetal malformations or death via reduced or delayed cellular growth.
2,4,5-Trichlorophenoxyacetic Acid↗
Developmental toxicity of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). I. Multireplicated dose-response studies in four inbred strains and one outbred stock of mice.
A large-scaled multireplicated developmental toxicity study was conducted in various strains/stocks of mice with the herbicide, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), by gavage on Gestational Days 6 through 14. The most important attributes of the study design were replicated test groups, a minimum of four dose levels per replicate, use of multiple stocks/strains of animals to obtain an estimate of the range in sensitivities due to genotype, complete pathological evaluation of maternal animals, and histopathological as well as teratological evaluation of the fetuses. Developmental toxicity was observed at doses below those producing discernible or measurable maternal toxicity. Regression and/or probit analyses were conducted to determine whether a dose-response relationship existed. Reduced fetal weight and increased incidence of cleft palate and embryolethality were the most significant prenatal effects of 2,4,5-T exposure observed in this study. Each strain/stock exhibited a dose-related decrease in fetal weight with the CD-1 mice having the steepest slope and the A/J mice having the shallowest slope. There was a striking similarity among the slopes of the dose-response curves for the various strains/stocks. The mean incidence of embryolethality in the A/J strain was significantly greater than that of the other strains or stocks. There was substantial variation among replicates within strains. The use of the replicated study design was logistically necessary due to the magnitude of the study and it also served to increase the statistical power of the study.
2,4,5-Trichlorophenoxyacetic Acid↗
Relationship between the shape of dose-response curves and background tumor rates.
Various authors have argued that a chemical which augments a carcinogenic process, which is already producing tumors spontaneously, will produce an increase in tumors no matter how small the dose. For this situation, no threshold dose exists whether or not the chemical is genotoxic. Under such conditions, it is expected that the dose-response will contain a linear term. A large database of animal bioassays (Gold et al., 1984) was examined to study the relationship between the shape of dose-response curves and the background tumor rate. The multistage model was fit to 143 data sets from 75 different chemicals. As expected, the presence of the linear term was correlated with the background tumor rate and the presence of higher degree terms in dose (cubic or greater) decreased as the background rate increased. This examination of a large number of chronic bioassay results appears to support the premise that low dose linearity is generally expected for tumor sites where background tumors occur, even for carcinogens which were negative by the Salmonella genotoxicity test.
Animals↗
Incidence of developmental defects at the no observed adverse effect level (NOAEL).
Bioassay data from Teratology, Vol. 1 (1968) through Vol. 40 (1990), were utilized which were sufficient to establish no observed adverse effect levels (NOAEL's) for 120 experiments on 93 developmental toxicants in animals. The observed incidence (risk) at the NOAEL was calculated as the proportion of affected fetuses minus the proportion affected in the control animals. This calculation did not require any dose-response modeling. Data were primarily from experiments on rats and mice with a few studies on rabbits and hamsters. There did not appear to be differences in risks at the NOAEL among these four species. For each experiment, the risk at the NOAEL was tabulated for all of the adverse effects which shared the same NOAEL. Since the observed risk at the NOAEL for either dead/resorbed or abnormal fetuses exceeded 1% in about one-fourth of the cases, this suggests that a benchmark dose with a risk on this order would eliminate the higher risks and serve as a basis for establishing reference doses. If the lower confidence limit on a benchmark dose is used in place of the NOAEL, better experimental designs with more animals would result in tighter confidence limits, giving larger (less stringent) reference doses than poorer experiments.
Abnormalities, Drug-Induced↗
An in vitro pancreas acinar cell model for testing the modulating effects of caloric restriction and ageing on cellular proliferation and transformation.
Pancreatic acinar cells were isolated for culture from a young (Y) and an old (O) Brown-Norway or Fischer 344 rat fed an ad libitum (AL) or calorically restricted (CR) diet. The cells were cultured and cellular growth rates were determined as a function of passage number. An overall increase in cellular growth rate and transformation frequency with age and/or AL diet relative to youth as well as a decrease with CR diet were concordant with reported responses in vivo. Transformation frequency was measured in Brown-Norway cells and followed the same pattern as the growth response: AL/O > AL/Y = CR/Y > CR/O. The cellular model is shown to fit the general multistage requirements of the carcinogenic process as well as general age and diet characteristics of pancreatic cancer. This pancreatic acinar cell age-diet approach may prove to be a valuable tool for determining mechanisms of exocrine pancreatic carcinogenesis as well as other disease states; it may also be of utility in in vitro gerontological nutritional and pharmacological studies since some of the age and diet determinants of biological effects appear to be segregable. Propensity of cells from an old and/or AL diet animal for faster growth and for cellular transformation are programmed into the cells by the time of their excision from the animal (as late as 14 months), indicating a heritable component in the model or a mechanism that is dependent upon elements that control gene expression.
Aging↗
Application of biomarkers to risk assessment.
Due to difficulties in conducting epidemiological studies, most estimates of cancer risk are based on data from animal bioassays. Extrapolation of cancer risk estimates in animals to humans requires an assumption of equal potency across species based on the average daily dose. The purpose of this paper is to examine the ability to predict tumor incidence across species from DNA adduct concentrations resulting from exposure to carcinogens. A 100-fold range of structurally diverse adduct concentrations corresponding to the same tumor incidence raises questions about quantitative predictability across chemical classes and across species. Differences in adduct structure, mutagenic efficiency, adduct repair rates, and cellular proliferation could account for some of the differences. For specific carcinogen-DNA adducts, the steady-state levels associated with a 50% tumor incidence appear to vary over a narrower range. An equal incidence of liver tumors was obtained at equal concentrations of aflatoxin B1-DNA adducts for rats and trout. A 2- to 3-fold range of 4-aminobiphenyl-DNA adduct concentrations between mice and dogs appears to be associated with nearly equal bladder tumor incidence, on the basis of limited data. In humans, a 5-fold higher concentration of a 4-aminobiphenyl-DNA adduct in bladders of smokers than of nonsmokers is compatible with the relative risk of bladder cancer due to smoking. DNA adduct concentrations certainly can be used to improve quantification of chemical exposures for epidemiological studies. Although promising, more data are needed to judge the usefulness of DNA adduct concentrations to predict cancer incidence across species.
Animals↗
Carcinogenic potency correlations: real or artifactual?
It has been suggested by various investigators that observed interspecies correlations of carcinogenic potency estimates based on bioassays are to a degree due to tautologous aspects of experimental designs. Some authors have even suggested that carcinogenic potency estimates derived from chronic bioassays are little more than experimental design artifacts. In this paper it is argued that constraints imposed by the use of the one-hit model to estimate carcinogenic potency are more restrictive than potential experimental design constraints.
Animals↗
Bladder and liver tumorigenesis induced by 2-acetylaminofluorene in different F1 mouse hybrids: variation within genotypes and effects of using more than one genotype on risk assessment.
Several F1 mouse hybrids were used in a chronic bioassay to determine whether such an experimental design would provide greater statistical power than using only the B6C3F1 hybrid. For this purpose, the dose response of formation of hepatocellular and bladder tumors after 30 mo of feeding 2-acetylaminofluorene (2-AAF) in the diet was assessed in 4 F1 mouse hybrids, including the B6C3F1 hybrid. No strain background-related differences in frequency of bladder neoplasms between any F1 hybrids were detected. Bladder tumors occurred only at the highest 2-AAF dose in female mice. In males the lowest dose was already sufficient to induce bladder neoplasms with incidences of 25-48% adjusted for different nontumor mortality patterns across doses. No marked strain-related differences in hepatocellular tumor rates were apparent in either sex. Higher frequencies of hepatocellular neoplasms were observed among the untreated control males of the B6C3, AY, and CVA F1 hybrids than among the comparable females. Among treated mice, the lowest 2-AAF dose increased liver tumor incidence, more so among the females than among the males. The different background genomes resulted in somewhat different risk assessments for liver tumor formation in males due to differences in the time-to-tumor curves. Except for the much higher background liver tumor rate in the CVY mice, the adjusted liver tumor incidences were similar across the four hybrids. Hence, the levels of statistical significance obtained for dose-response trends and comparisons of treated and control groups were similar using 48 animals per dose groups with B6C3 mice, or combinations of 24 animals per dose from 2 genotypes, or 12 animals per dose from the 4 hybrid genotypes. Estimates of carcinogenic potency for bladder tumors were similar, within a factor of two, across the four hybrids. However, estimates of liver tumor potency across genotypes varied by a factor of two and six for females and males, respectively. Thus, the mean of cancer potency estimates across these genotypes would be more representative for mice than results from any single genotype. As in chronic carcinogenesis studies with other test agents, neoplasms developed in only a certain proportion, rather than in all, of the genetically identical animals exposed to a given dose of the toxicant for the same length of time under the same controlled environmental conditions. This phenotypic variability in toxic responses may reflect differential regulation of gene expression among the genetically identical test animals.
2-Acetylaminofluorene↗