If the broad spectrum of mechanistic research conducted on an environmental carcinogen is to be used in quantifying cancer risks, statisticians must play a key role. Statistical methods are critically needed for a scientifically valid analysis of a complicated series of linked experimental findings. This will require a greater understanding of the underlying biology than is common in statistical consulting, aiding in the development of complicated mechanistically based mathematical descriptions of mean response and in the creation of statistical methods for the estimation of model parameters (e.g. likelihoods) able to use both the underlying model and much of the available data.
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References
1.
Barrett JC , Wiseman RW.Cellular and molecular mechanisms of multistep carcinogenesis: relevance to carcinogen risk assessment . Environmental Health Perspectives1987; 76: 65-70 .
2.
Boulikas T.Phosphorylation of transcription factors and control of the cell cycle . Critical Reviews in Eucaryotic Gene Expression1995; 5: 1-77 .
3.
Bian X , Hughes FM Jr , Huang Y , Cidlowski JA , Putney JW Jr.Roles of cytoplasmic Ca+2 and intracellular Ca+2 stores in induction and suppression of apoptosis in S49 cells . American Journal of Physiology1997; 272: C1241-C1249 .
4.
Ito N , Hasegawa R , Imaida K , Hirose M , Shirai T.Medium-term liver and multi-organ carcinogenesis bioassays for carcinogens and chemopreventive agents . Experimental and Toxicological Pathology1996; 48: 113-119 .
5.
Weinberg RA.How cancer arises . Scientific American1996; 275: 62-70 .
6.
Ganz PA , Coscarelli A , Fred C , Kahn B , Polinsky M , Petersen L.Breast cancer survivors: psychosocial concerns and quality of life . Breast Cancer Research and Treatment1996; 38: 183-199 .
7.
Law MR , Morris JK , Watt HC , Wald NJ.The dose-response relationship between cigarette consumption, biochemical markers and risk of lung cancer . British Journal of Cancer1997; 75: 1690-1693 .
8.
Franceschi S , Favero A , La Vecchia C , Negri E , Dal Maso Li , Salvini S , Decarli, A , Giacos A.Influence of food groups and food diversity on breast cancer risk in Italy . International Journal of Cancer1995; 11: 785-789 .
9.
Kopp-Schneider A.Carcinogenesis models for risk assessment . Statistical Methods in Medical Research1997; 6: 317-340 .
10.
Bailer A , Dankovic D.An introduction to the use of physiologically based pharmacokinetic models in risk assessment . Statistical Methods in Medical Research1997; 6: 341-358 .
11.
Kohn M , Lucier G , Clark G , Sewall C , Tritscher A , Portier C.A mechanistic model of the effects of dioxin on gene expression in the rat liver . Toxicology and Applied Pharmacology1993; 120: 138-154 .
12.
Kohn M , Sewall C , Lucier G , Portier C.A mechanistic model of effects of dioxin on thyroid hormones in the rat . Toxicology and Applied Pharmacology1996; 165: 29-48 .
13.
Beatty DA , Piegorsch WW.Optimal statistical design for toxicokinetic studies . Statistical Methods in Medical Research1997; 6: 359-376 .
14.
Kopp-Schneider A , Portier CJ , Sherman CD.The exact formula for tumor incidence in the two-stage model . Risk Analysis1994; 14: 1079-1080 .
15.
Hanin L , Yakovlev A.A nonidentifiability aspect of the two-stage model of carcinogenesis . Risk Analysis1996; 16: 711-715 .
16.
Sherman C , Portier C.The two-stage model of carcinogenesis: overcoming the nonidentifiability dilemma . Risk Analysis1997; 17: 367-374 .
17.
Kopp-Schneider A , Portier CJ.Distinguishing between models of carcinogenesis: the role of clonal expansion . Fundamental and Applied Toxicology1991; 17: 601-613 .
18.
Armitage P , Doll R.The age distribution of cancer and a multistage theory of carcinogenesis . British Journal of Cancer1954; 8: 1-12 .
19.
Chu KC , Brown CC , Tarone RE , Tan WY.Differentiating among proposed mechanisms for tumor promotion in mouse skin with the use of the multievent model for cancer . Journal of tbe National Cancer Institute1987; 79: 789-796 .
20.
Dewanji A , Venzon D , Moolgavkar S.A stochastic two-stage model for cancer risk assessment. II. The number and size of premalignant clones . Risk Analysis1989; 9: 179-187 .
21.
Kopp-Schneider A , Portier CJ.Birth and death/differentiation rates of papillomas in mouse skin . Carcinogenesis1992; 13: 973-978 .
22.
Portier CJ , Kopp-Schneider A , Sherman CD.Calculating tumor incidence rates in stochastic models of carcinogenesis . Mathematical Biosciences1996; 135: 129-146 .
23.
Dewanji A , Moolgavkar S , Luebeck E.Two-mutation model for carcinogenesis: joint analysis of premalignant and malignant lesions . Mathematical Biosciences1991; 104: 97-109 .
24.
Kopp-Schneider A , Portier CJ.Carcinoma formation in mouse skin painting studies is a process with greater than two-stages . Carcinogenesis1995; 16: 53-59 .
25.
Solb W , Janssen PHM , van den Hof JM.Structural identifiability of PBPK models: practical consequences for modeling strategies and study designs . Critical Reviews in Toxicology1997; 27: 261-272 .
26.
Bevan D , Weyand E.Compartmental analysis of the disposition of benzo[a]pyrene in rats . Carcinogenesis1988; 9: 2027-2032 .
27.
Clewell H , Lee Ti , Carpenter R.Sensitivity of physiologically based pharmacokinetic models to variation in model parameters: methylene chloride . Risk Analysis1994; 14: 521-531 .
28.
Williams P.Structural identifiability of pharmacokinetic models - compartments and experimental design . Journal of Veterinary Pharmacology and Therapy1990; 13: 121-131 .
29.
Krewski D , Wang Y , Bartlett S , Krishnan K.Uncertainty, variability, and sensitivity analysis in physiological pharmacokinetic models . Journal of Biopharmaceutical Statistics1995; 5: 245-271 .
30.
Lee W , Lin R.Analysis of cancer rates using excess risk age-period-cohort models . International Journal of Epidemiology1995; 24: 671-677 .
31.
Lyles C. The modeling of cell proliferation: Incorporating the cell cycle. Doctoral dissertation, University of North Carolina, Chapel Hill, 1996.
32.
Sherman C , Portier C , Kopp-Schneider A.Multistage models of carcinogenesis: an approximation method for the size and number distribution of late-stage clones . Risk Analysis1994; 14: 1039-1048 .
33.
Sherman C , Portier C.A biologically-based mathematical model of colon carcinogenesis: the multipath/multistage model . Informatik, Biometrie und Epidemiologie in Medizin und Biologie1996; 25: 250-254 .
34.
Liu S. Parameter estimation in a two-stage model of carcinogenesis. Doctoral dissertation, University of North Carolina, Chapel Hill, 1993.
35.
Moolgavkar S.Model for human carcinogenesis: action of environmental agents . Environmental Health Perspectives1983; 50: 285-291 .
36.
Moolgavkar SH , Luebeck EG , de Gunst M , Port RE , Schwarz M.Quantitative analysis of enzyme-altered foci in rat hepatocarcinogenesis experiments I: single agent regimen . Carcinogenesis1990; 11: 1271-1278 .
37.
Portier CJ , Kohn MC , Kopp-Schneider A , Sherman CD , Maronpot R , Lucier GW.Modeling the number and size of hepatic focal lesions following exposure to 2,3,7,8-TCDD . Toxicology and Applied Pharmacology1996; 138: 20-30 .
38.
Hennings H , Yuspa SH.Two-stage tumor promotion in mouse skin: an alternative interpretation . Journal of the National Cancer Institute1985; 74: 735-740 .
39.
Vogelstein B , Fearon E , Hamilton Set al.Genetic alterations during colorectal-tumor development . New England Journal of Medicine1988; 319: 525-532 .
40.
Sherman C , Portier C.Quantitative analysis of multiple phenotype enzyme-altered foci in rat hepatocarcinogenesis experiments: the multipath/multistage model of carcinogenesis . Carcinogenesis1995; 16: 2499-2506 .
41.
Bucher J.National Toxicology Program studies: principles of dose selection and applications to mechanistic based risk assessment . Fundamental and Applied Toxicology1996; 31: 1-8 .
42.
Portier C , Edler L.Two-stage models of carcinogenesis, classification of agents and design of experiments . Fundamental and Applied Toxicology1990; 14: 444-460 .
43.
Kodell R.Bioassay designs for validating biologically based mathematical models of carcinogenesis for risk assessment . Drug and Metabolites Review1996; 28: 219-223 .
44.
Portier CJ.Biostatistical issues in the design and analysis of animal carcinogenicity experiments . Environmental Health Perspectives1994; 102(suppl 1): 5-8 .
45.
Goddard MJ , Krewski D.The future of mechanistic research in risk assessment - where are we going and can we get there from here . Toxicology1995; 102: 53-70 .
46.
Moolgavkar S , Luebeck G.2-Event model for carcinogenesis - biological, mathematical, and statistical considerations . Risk Analysis1990; 10: 323-341 .
47.
Sexton K , Reiter LW , Zenick H.Research to strengthen the scientific basis for health risk assessment - a survey of the context and rationale for mechanistically based methods and models . Toxicology1995; 102: 3-20 .
48.
Zielinski JM , Krewski D , Goddard MJ , Wang Y.Experiment and biologically based models for cancer risk assessment . Drug Metabolism Reviews1996; 28: 53-75 .
49.
Kodell R , Chen J , Gaylor D.Neurotoxicity modeling for risk assessment . Regulatory Toxicology and Pharmacology1995; 22: 24-29 .
