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Investigating Carcinogen Risk Analysis Through Benzene Image from Matthew J. Dowd Department of Medicinal Chemistry Virginia Commonwealth University 2002 David M. Hassenzahl

Objective Use benzene as a case for investigating Toxicology Epidemiology Uncertainty Regulatory Science 2002 David M. Hassenzahl

Toolbox Building Likelihood Maximization Curve fitting Bootstrapping Z-Scores Relative Risk Dose-Response extrapolation 2002 David M. Hassenzahl

Overview of benzene Fairly normal hydrocarbon Manufacturing Petroleum items Strongly presumed human cancer-causing agent Animal measures Many epidemiological studies Leukemia as critical endpoint 2002 David M. Hassenzahl

Benzene structure Image from Matthew J. Dowd Department of Medicinal Chemistry Virginia Commonwealth University 2002 David M. Hassenzahl

Benzene Data in Should We Risk It? Toxicological Data, p. 175 et seq. Epidemiological Data p 211 – 216 But numerous other information sets Other toxicological information (uncommon) Chinese laborers Turkish specialists 2002 David M. Hassenzahl

Toxicology Data Set 2002 David M. Hassenzahl Crump and Allen 1984

What are dangers from benzene? Hazard as intensity times presentation How would we decide power? Extrapolate from creature information? Extrapolate from epidemiological information? How wrong will we be? What are "genuine" exposures? What are impacts at these levels? 2002 David M. Hassenzahl

Toxicology Paracelsus "the dosage makes the toxic substance" Regulatory presumptions! This is not Dr. Gerstenberger's Toxicology! 2002 David M. Hassenzahl

Reading SWRI Chapter 5 US EPA Proposed rules (US EPA 1996) Cox 1996 2002 David M. Hassenzahl

General thought Applied measurements Greater specificity about presentation than the study of disease transmission Observed impacts Artificial control of introduction 2002 David M. Hassenzahl

Physiologically Based Pharmacokinetics PBPK Investigate streams of materials through bodies System elements models More on these in introduction address 2002 David M. Hassenzahl

Studies Animals Rarely people Parts Cell tissue 2002 David M. Hassenzahl

Effects Chronic growth casualty expanding enthusiasm for different issues lead and insight in kids. Intense Reversible Irreversible 2002 David M. Hassenzahl

Crump and Allen Benzene information set Animals at different fixations Four information focuses "Fashioner" mice 2002 David M. Hassenzahl

Relevance to Humans How to get from abnormal state, lifetime investigations of creatures to expected low measurement impacts in people? 2002 David M. Hassenzahl

Questions about benzene Is benzene a mouse cancer-causing agent? Is benzene a human cancer-causing agent? Assuming this is the case, how powerful? 2002 David M. Hassenzahl

Benzene information set I Crump and Allen information set (Crump and Allen 1984) Note: the genuine measurements are not expressed effectively here. See "notes for more data 2002 David M. Hassenzahl

Benzene information set II 1.0 0.8 0.6 P(cancer) 0.4 0.2 0 25 50 75 100 Dose (mg/kg/day) Crump and Allen information set . 2002 David M. Hassenzahl

Uncertainty Pervades Often downplayed Creates (or possibly delays) strife Think as we go! (Some portion of Homework PS 2) 2002 David M. Hassenzahl

Animal Test Issues Interspecific correlation Statistical vulnerability Heterogeneity Extrapolation Dose Metric 2002 David M. Hassenzahl

Interspecific examination Mouse-human Metabolism as an element of body weight Dose human = sf Dose mouse sf = (BW human/BW mouse ) 1 b is exactly determined as 0.75 an a. See SWRI page 177. 2002 David M. Hassenzahl

Interspecific correlation Lifetime of human = lifetime mouse? Mice age 30 days for every human day Total mouse lifetime is much shorter Analogous organs or procedures? Do mice have growth focuses we don't? Do we have tumor focuses mice don't? a. See SWRI page 177. 2002 David M. Hassenzahl

Interspecific examination 1. Hallenbeck, 1993 2. Finley et al., 1994 2002 David M. Hassenzahl

Interspecific examination sf = (BW human/BW mouse ) 1-b sf = (70/0.03) 0.25 = 7.0 Dose human = 7.0 Dose mouse 2002 David M. Hassenzahl

Interspecific correlation Crump and Allen information set, changed over to people 2002 David M. Hassenzahl

Animal Test Issues Interspecies examination Statistical vulnerability Heterogeneity Extrapolation Dose Metric 2002 David M. Hassenzahl

Binomial Distribution 50 hereditarily "indistinguishable" mice… binomial conveyance? Can utilize this to produce "probability capacity" to look at the probability that any given likelihood is 2002 David M. Hassenzahl

Likelihood Maximization More suitable than Least Squares when you know something about probabilities "Bootstrapping" technique required We will work through probability amplification 2002 David M. Hassenzahl

Statistical Uncertainty Can figure standard deviation utilizing the binomial Recall that two standard deviations to either side speaks to a 95% certainty interim, and... 2002 David M. Hassenzahl

Statistical Uncertainty 1.0 0.8 0.6 P(cancer) 0.4 0.2 0 175 350 525 700 Human Dose (mg/kg/day) Crump and Allen information set, connected to people 2002 David M. Hassenzahl

Animal Test Issues Interspecies examination Statistical vulnerability Heterogeneity Extrapolation Dose Metric 2002 David M. Hassenzahl

Heterogeneity Epidemiology and toxicology Genetically indistinguishable mice contrasted with various people Predictable versus flighty helplessness Male and female contrasts (watched growth rates are distinctive) 2002 David M. Hassenzahl

Heterogeneity Genetic assorted qualities among people Early bits of knowledge into tumor instrument: subpopulation conceived with one of two "stages" contended Variability as a component of age 2002 David M. Hassenzahl

Animal Test Issues Interspecies examination Statistical instability Heterogeneity Extrapolation Dose Metric 2002 David M. Hassenzahl

Extrapolation Theoretical or "Robotic" models: one-hit two-hit two-organize Empirical Cox "information driven, demonstrate free bend fitting" EPA Proposed Guidelines 2002 David M. Hassenzahl

Overestimation Tautological effects Thresholds Hormesis, or "Vitamin" impact Underestimation Saturation Synergistic impacts Susceptibility Omission Extrapolation Concerns 2002 David M. Hassenzahl

2002 David M. Hassenzahl

After EPA (1996) 2002 David M. Hassenzahl

Statistical Uncertainty 1.0 0.8 0.6 P(cancer) 0.4 0.2 0 175 350 525 700 Human Dose (mg/kg/day) Crump and Allen information set, connected to people 2002 David M. Hassenzahl

1.0 LED(10) = 100 mg b/kg/day 0.8 0.6 P(cancer) 0.4 0.2 0 175 350 525 700 Human Dose (mg/kg/day) 2002 David M. Hassenzahl

Extrapolation If LED(10) = 100 mg/kg/day, then LED(10 - 6 ) = 100 10 - 6/0.1 = 1 10 - 4 mg/kg/day 2002 David M. Hassenzahl

Animal Test Issues Interspecies examination Statistical vulnerability Heterogeneity Extrapolation Dose Metric 2002 David M. Hassenzahl

Dose Metric Assumption: presentation is unessential to impact Area under the bend/expected esteem. Lifetime measurements prompts to normal every day dosage. Especially risky if there are limit impacts or outrageous impacts 2002 David M. Hassenzahl

Risk to Humans? Lifetime malignancy hazard 40 hours for every week 50 weeks for every year 30 years Average 10 ppm(v) introduction? 2002 David M. Hassenzahl

Calculate Risk 10ml benzene/liter air 0.313 ml/mg 20m 3 air/day 1000 liters/m 3 70kg man 2002 David M. Hassenzahl

Cancer Risk Lifetime Cancer Probability is a component of Dose and Potency Assume aggregate measurements Use Daily Dose per kg body weight, found the middle value of over lifetime Potency normally given as q* Additional hazard per unit dosage 2002 David M. Hassenzahl

Cancer Risk: Exposure Term 2002 David M. Hassenzahl

Computed Exposure Terms 2002 David M. Hassenzahl

Computed Exposure Terms 2002 David M. Hassenzahl

Cancer Risk 2002 David M. Hassenzahl

"Administrative Science" Issues Neither a straightforward question nor a thoughtless approach (albeit regularly expressed this way) "Human wellbeing traditionalist" versus "Substantial hand of preservationist suppositions?" May be overestimates May be disparages 2002 David M. Hassenzahl

Regulatory Toxicology "Genuine hazard" is a reified chance ALL evaluations, including focal propensities, are likely wrong More science does not ensure "less hazard" "less instability" 2002 David M. Hassenzahl

Likelihood Maximization A bend fitting strategy 2002 David M. Hassenzahl

Binomial Distribution 50 hereditarily "indistinguishable" mice… binomial circulation? Can utilize this to produce "probability work" for an anticipated result given a watched result 2002 David M. Hassenzahl

Likelihood Maximization More fitting than Least Squares when you know something about probabilities "Bootstrapping" technique required 2002 David M. Hassenzahl

Statistical Uncertainty Can compute standard deviation utilizing the binomial Recall that two standard deviations to either side speaks to a 95% certainty interim, and... 2002 David M. Hassenzahl

Statistical Uncertainty 1.0 0.8 0.6 P(cancer) 0.4 0.2 0 100 200 300 400 Human Dose (mg/kg/day) Crump and Allen information set, connected to people 2002 David M. Hassenzahl

Counting Rules What is the probability of g

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