Age-Related Differences in Susceptibility to Carcinogenesis—Toward an Improved Analysis of Data on Age-Related Differences in Cancer Sensitivity in the EPA Children’s Cancer Risk Guidance Document Researchers: Dale Hattis, Principal Investigator Rob Goble, Research Professor Abel Russ, Research Associate Jen Ericson and Jill Mailloux, Student Research Assistants Margaret Chu, EPA Project Monitor nions are mine and do not necessarily reflect EPA p
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Researchers: Dale Hattis, Principal Investigator Rob Goble, Research Professor
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Age-Related Differences in Susceptibility to Carcinogenesis—Toward an Improved Analysis of Data on Age-Related Differences in Cancer Sensitivity in the EPA Children’s
Cancer Risk Guidance Document
Researchers:Dale Hattis, Principal Investigator
Rob Goble, Research ProfessorAbel Russ, Research Associate
Jen Ericson and Jill Mailloux, Student Research Assistants
Margaret Chu, EPA Project Monitor
Opinions are mine and do not necessarily reflect EPA policy
INNOVATIVE ASPECTS OF THE ANALYSIS --Paper #1
• Compare measures of potency, rather than uncorrected cancer incidence, among groups.
• Where dosage spans multiple age groups, use dummy variables to represent the observed tumor risk as the sum of cancer contributions from dosing in different periods:– The periods are: fetal (gd 12-19), pre-weaning (1-21 d); weaning - 2 mo;
adult (2 mo - 2 yr).– Where continuous dosing occurs in only a fraction of a period that
fraction is used as the corresponding “dummy” rather than 1.• Use likelihood methods to first derive appropriate statistical
weighting of the different observations, and to avoid bias from excluding “0” points.
• Express dosage for animals of different weights on a metabolically consistent basis (either concentration in air or food, or per unit body weight to the three quarters power).
Paper #2--Monte Carlo Analysis of Uncertainties for Application to Human Risk Assessments
• Uncertainties in the central estimates of the sensitivities of each life stage per dose in mg/kg^3/4, relative to adults
• Uncertainties from chemical-to-chemical differences in life-stage related sensitivities
• Uncertainties in the mapping of comparative ages/times between rodents and humans
• Bottom line:--Overall expected increment to lifetime tumor risks from full lifetime constant exposure per mg/kg^3/4
The Poisson One-hit Transformation--From the Fraction of Animals with at Least One Tumor to The
Number of Tumors Per Animal
Fraction of Animals With Tumors = Ptumor = 1 - PNo Tumor
PNo Tumor = e-m where m = tumor "hits"/animalsolving for m:m =-ln(PNo Tumor) = - ln(1- Fraction of Animals With Tumors)
Effect of the One-Hit Transformation for Various Observations of % Tumors in Animal Groups
Fract Animals with Tumors at
a Site
Tumor Transformations
/Animal0.01 0.0100.1 0.105
0.25 0.2880.4 0.511
0.55 0.7990.7 1.204
0.85 1.8970.9 2.303
0.95 2.996
Use of Part-Period Dummy Variables in Combination To Represent Different Exposure Patterns--Maltoni Vinyl
Chloride Experiments
Exposure GroupBirth-weaning
(21 d) Weaning-2 mo AdultControl 0 0 0.000
5 weeks exposure beginning at birth 1 0.359 0.0005 weeks exposure beginning at 11 weeks of age 0 0 0.04352 weeks of exposure beginning at 13 weeks of age 0 0 0.411
Detailed Model for Statistical Fitting
€
Fraction with tumors = 1 - e- B + A(a + fF + cC + wW) ⎡
⎣ ⎢ ⎤ ⎦ ⎥
Where :B = group background transformations per animalA = group adult transformations per animal at the highest adult dose ratea = fraction of the adult period with dosing at the maximum adult rate (this term reflects an adjustment for cases where a group received less than the full adult dosing rate)f = fraction of the fetal period with dosing at the maximum adult rate (also adjusted for dose rate as needed)F = fetal/adult sensitivity ratioc = fraction of the birth - weaning period with dosing at the maximum adult rate (also adjusted for dose rate as needed)C = birth - weaning/adult sensitivity ratiow = fraction of the weaning - 60 day period with dosing at the maximum adult rate (also adjusted for dose rate as needed)W = weaning - 60 day/adult sensitivity ratio
Summary Results of Analyses for Paper #1
• Central estimate results: 5-60 fold increased carcinogenic sensitivity in the birth-weaning period per dose/(body weight3/4-day) for mutagenic carcinogens--no detectable increase for nonmutagens
• Somewhat smaller increase—about 5 fold—for radiation carcinogenesis per Gray
• Greater increase for mutagens for continuous, rather than discrete dosing protocols
• Greater increase in males than females• Similar increased sensitivity in the fetal period for direct-acting
nitrosoureas, but no such increased fetal sensitivity for carcinogens requiring metabolic activation
• Greater increase in early life sensitivity in liver, and less in lung, than for other tumor sites.
Overview of the Data Base
Dose Groups With Exposures in Specific Life Stages (and
numbers of animals*tumor-site observations in parentheses)
Geometric Mean Ratios of Child/Adult Clearance/BodyWeight and Clearance/Body Weight3/4. Data RepresentRegression Results from 104 Data Groups for 27 Drugs forHumans in Various Age Groups (with ± 1 Standard ErrorRanges in Parentheses)
Form for ExpressingTotal Body Clearance
Prematureneonates
Full termneonates
1 wk - 2mo
2 - 6 mo 6 mo - 2yr
2 -12 yr 12 - 18 yr
Mg/Kg Body Weight 0.52(0.43-0.63)
0.66(0.61-0.73)
0.77(0.71-0.84)
1.21(1.06-1.39)
1.71(1.52-1.92)
1.42(1.31-1.53)
0.97(0.78-1.20)
Mg/(Kg BodyWeight)3/4
0.23(0.19-0.28)
0.31(0.28-0.34)
0.38(0.35-0.42)
0.68(0.59-0.78)
1.03(0.91-1.17)
1.08(1.00-1.17)
0.93(0.74-1.17)
Overall Results--Continuous vs Discrete Dosing Protocols (Caveat: Continuous dosing results include 4/9 nonmutagens)
All Continuous Chemical Dosing Experiments (based on a total of 151group tumor incidence observations for 9 chemicals).
MLE for cancer inductions perdose/(body weight.75 -day) relative
to adults 95% LCL 95% UCL
Fetal Period (8days beginningGD 12) 4.9 0.5 9.3
Birth-Weaning (21days) 8.7 6.5 10.8
Weaning-60 days(39 days) 0.000 0.000 0.24
All Discrete Chemical Dosing Experiments (based on a total of 274 grouptumor incidence observations for 6 chemicals).
MLE for cancer inductions perdose/(body weight.75 -day) relative
to adults 95% LCL 95% UCL
Fetal Period (8days beginningGD 12) 5.1 3.6 8.5
Birth-Weaning (21days) 10.5 7.2 16.2
Weaning-60 days(39 days) 1.51 1.03 2.3
Overall Results--Radiation Exposures
All Ionizing Radiation Dosing Experiments (based on a total of 138 grouptumor incidence observations for 4 radiation types).
Maximum likelihood estimate ofcancer inductions per dose in rads
or Gray relative to comparablydosed adults 95% LCL 95% UCL
Fetal Period (8days beginningGD 12) 3.5 2.2 5.7
Birth-Weaning (21days) 5.3 3.9 8.3
Weaning-60 days(39 days) 2.4 1.8 3.4
Age-Related Pharmacodynamic Sensitivity for Carcinogenesis--Mutagens vs Non-Mutagens--Continuous Dosing Protocols
Chemicals Classified by EPA as Mutagenic (5 compounds, 43 tumorincidence observations):
MLE of cancer inductions perdose/(body weight.75 -day) relative
to adults 95% LCL 95% UCL
Fetal 8.4 3.5 15.5
Birth-Weaning 24 17.1 34
Weaning-60 days 3.7 0.0 9.1
Chemicals Classified by EPA as Not Mutagenic (4 compounds, 108 tumorincidence observations in animal groups):
MLE of cancer inductions perdose/(body weight.75 -day) relative
to adults 95% LCL 95% UCL
Fetal 0.0 0.0 17.4
Birth-Weaning 3.0 0.0 4.7
Weaning-60 days 0.0 0.0 2.0
Different Results for Mutagens by Sex--Continuous + Discrete Dosing Data Combined
Male Animals (9 compounds, 153 tumor incidence observations):Maximum likelihood estimate of cancerinductions per dose/(body weight.75 -day)
relative to comparably dosed adults95%LCL
95%UCL
ArithmeticMean
Fetal 25 15.6 42 27
Birth-Weaning 57 38 90 59
Weaning-60 days 5.0 3.1 8.6 5.3
Female Animals (9 compounds, 153 tumor incidence observations):Maximum likelihood estimate of cancerinductions per dose/(body weight.75 -day)
relative to comparably dosed adults95%LCL
95%UCL
ArithmeticMean
Fetal 1.77 1.05 2.9 1.83
Birth-Weaning 4.4 3.3 6.0 4.5
Weaning-60 days 0.82 0.50 1.29 0.85
Females--Lognormal Plots of Likelihood-Based Uncertainty Distributions for Cancer Transformations Per Daily Dose for Various
Life Stages for Mutagenic Chemicals (Relative to Comparable Exposures of Adults)--Discrete + Continuous Dosing Experiments
210-1-2
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Fem Mut Log(Birth-Wean/Adult)
Fem Mut Log(Fetal/Adult)
Fem Mut Log(Wean-60d/Adult)
Z-Score
Fem Mut Log(Period/Adult Risk Per Daily Dose/BW^3/4)
y = 0.646 + 0.0785x R^2 = 1.000
y = 0.246 + 0.134x R^2 = 1.000
y = - 0.0880 + 0.124x R^2 = 0.999
No difference from adult risk
3X greater than adult risk
95% Lower Confidence Limits
95% Upper Confidence Limits
Males--Lognormal Plots of Likelihood-Based Uncertainty Distributions for Cancer Transformations Per Daily Dose for Various
Life Stages for Mutagenic Chemicals (Relative to Comparable Exposures of Adults)--Discrete + Continuous Dosing Experiments
210-1-2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
Male Mut Log(Birth-Wean/Adult)
Male Mut Log(Fetal/Adult)
Male Mut Log(Wean-60d/Adult)
Z-Score
Male Mut Log(Period/Adult Risk Per Daily Dose/Body Weight^3/4)
y = 1.76 + 0.113x R^2 = 0.999
y = 1.41 + 0.132x R^2 = 1.000
y = 0.705 + 0.133x R^2 = 0.999
10x greater than adult risk
30x greater than adult risk
95% Lower Confidence Limits
95% Upper Confidence Limits
Direct-Acting vs Metabolically-Activated Mutagens--Standard Age Periods, Discrete Dosing Experiments
Direct-Acting--Ethylnitrosourea and Methylnitrosourea (108 tumorincidence observations):
MLE of cancer inductions perdose/(body weight.75 -day) relative
to adults 95% LCL 95% UCL
Fetal 11.6 5.4 25
Birth-Weaning 10.2 5.1 21
Weaning-60 days 2.7 1.37 5.6
Metabolically-Activated Mutagenic Carcinogens (Benzo(a)pyrene,dethylnitrosamine, dimethylbenzanthracene, and urethane, 166 tumorincidence observations in animal groups):
MLE of cancer inductions perdose/(body weight.75 -day) relative
to adults 95% LCL 95% UCL
Fetal 0.21 0.01 0.90
Birth-Weaning 15.0 8.4 33
Weaning-60 days 1.24 0.76 2.3
Direct-Acting vs Metabolically-Activated Mutagens--Narrower Age Periods, Discrete Dosing Experiments
Direct-Acting Mutagenic Carcinogens--Ethylnitrosourea and Methylnitrosourea (108tumor incidence observations):
MLE of cancer inductions perdose/(body weight.75 -day) relative to
Detailed Results by Life Stage For Females--Uncertainty Distributions of Risks for Full Lifetime Exposures to a Generic Mutagenic Carcinogen at a Constant Dose Rate Per Kg of Body
Weight3/4 (The numbers represent the increment to lifetime relative risk/dose where the risk for the full adult period is 1)
Percentile ofUncertaintyDistribution
Female Fetal PeriodRisk Relative to
Adult Period
Female Birth-WeaningPeriod Risk Relative to
Adult PeriodFemale Weaning-60d PeriodRisk Relative to Adult Period
Overall Bottom Line--Population Expected Risks from Lifetime Constant Exposure to a Mutagenic Carcinogen per Body Weight^3/4 Relative to Adult-Only Exposure
Percentile ofUncertaintyDistribution
Male Full LifetimeRisk Relative to
Adult Period Only
Female Full LifetimeRisk Relative to Adult
Period Only
Male and Female PopulationAverage Risk Relative to
Take-Home Conclusions From the Analysis of the Current Data Base
• Improved life-stage specific analyses of risks from mutagenic carcinogens are possible using current information.
• These involve appreciable uncertainties, particularly in the mapping of rodent exposure periods to human equivalents.
• The current analysis suggests that early-life exposure could make important contributions to full-life cancer risks. The mean estimate is a 3.5 fold increment to the risks for full life exposure per body weight^3/4 relative to adult-only exposure, with 5%-95% confidence limits of 1.7 - 7.4 fold. The increments will be somewhat less for constant daily dosage expressed on a mg/kg body weight basis.