EPA/63 0/R-03/003F
March 2005
Supplemental Guidance for Assessing Susceptibility from
Early-Life Exposure to Carcinogens
Risk Assessment Forum
U.S. Environmental Protection Agency
Washington, DC 20460
-------
AUTHORS AND CONTRIBUTORS
This document was prepared by a Technical Panel of the Risk Assessment Forum.
AUTHORS
Hugh Barton, National Health and Environmental Effects Research Laboratory, ORD
Jim Cogliano, National Center for Environmental Assessment, ORD
Michael P. Firestone, Office of Children's Health Protection, OA
Lynn Flowers, National Center for Environmental Assessment, ORD
R. Woodrow Setzer, National Health and Environmental Effects Research Laboratory,
ORD
Larry Valcovic, National Center for Environmental Assessment, ORD
Tracey Woodruff, Office of Policy, Economics, and Innovation, OA
CONTRIBUTORS
Neepa Choksi, Fellow to the Office of Solid Waste and Emergency Response
Resha M. Putzrath, Risk Assessment Forum Staff, National Center for Environmental
Assessment, ORD
William P. Wood, Risk Assessment Forum Staff, National Center for Environmental, ORD
11
-------
ACKNOWLEDGMENTS
We would especially like to thank David Bennett for his earlier work in leading the initial
efforts for this work, Bill Wood for his support, and Julian Preston for his helpful review of the
document. Special thanks also go to Rebecca Brown, Rosemary Castorina, Ellen Phelps, and
Linda Poore for their efforts in pulling together the underlying information.
in
-------
CONTENTS
PREFACE v
1. INTRODUCTION 1
2. PROCEDURES 6
2.1. DATA SOURCES FOR ANIMAL STUDIES 6
2.2. EVALUATING THE MODE OF ACTION OF CARCINOGENS 8
2.3. QUANTITATIVE METHODS 9
2.4. IONIZING RADIATION 12
3. RESULTS 13
3.1. QUALITATIVE EVALUATION OF THE DATABASE 13
3.2. QUANTITATIVE EVALUATION OF THE DATABASE 15
3.2.1. Carcinogens with a Mutagenic Mode of Action 16
3.2.1.1. Early Postnatal, Juvenile, and Adult Repeated Dosing Studies of Chemicals
with a Mutagenic Mode of Action 16
3.2.1.2. Acute Dosing Studies of Chemicals with a Mutagenic Mode of Action 17
3.2.2. Carcinogens with Modes of Action Other Than Mutagenicity 19
3.2.3. Ionizing Radiation 21
4. DISCUSSION 23
5. GUIDANCE FOR ASSESSING CANCER RISKS.FROM EARLY-LIFE EXPOSURE 30
6. COMBINING LIFESTAGE DIFFERENCES IN EXPOSURE AND DOSE-RESPONSE WHEN ASSESSING
CARCINOGEN RISK - SOME EXAMPLES FOR CARCINOGENS THAT ACT THROUGH A MUTAGENIC
MODE OF ACTION 36
6.1 CALCULATING LIFETIME RISKS ASSOCIATED WITH LIFETIME EXPOSURES 36
6.2 CALCULATING LIFETIME RISKS ASSOCIATED WITH LESS THAN LIFETIME EXPOSURES 368
APPENDIX A: TABLES A-l
Table la. Chemicals that have been found to have carcinogenic effects from prenatal or postnatal
exposure in animals as identified in different review articles A-l
Table Ib. List of chemicals considered in this analysis. (These are chemicals for which there are
both early-life and adult exposure reported in the same animal experiment.) A-3
Table 2. Methodological information and tumor incidence for animal studies with early
postnatal and juvenile and adult repeated exposures A-5
Table 3. Methodological information and tumor incidence for animal studies with early
postnatal and juvenile and adult acute exposure A-17
Table 4. Ratio of early-life to adult cancer potencies for studies with repeated exposures of
juvenile and adult animals to carcinogens with a mutagenic mode of action A-44
Table 5: Ratio of early-life to adult cancer potencies for studies with repeated exposures of
juvenile and adult animals to chemicals with other than mutagenic modes of action A-45
IV
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of
juveniles and adult animals to chemicals with mutagenic modes of action A-46
Table 7. Ratio of early-life to adult cancer potencies for studies with lifetime exposures starting
with juvenile and adult A-57
Table 8. Summary of quantitative estimates of ratio of early-life to adult cancer
potencies A-60
Table 9. Excess Relative Risk (ERR) estimates for cancer incidence from Life Span Study
(Japanese survivors) A-61
Table 10. Excess Relative Risk estimates for incidence of thyroid cancer from Life Span
Study A-62
Table 11. Coefficients for the Revised Methodology mortality risk model (from U.S. EPA,
1999) A-63
REFERENCES R-l
LIST OF FIGURES
Figure 1. Flow chart for early-life risk assessment using mode of action framework 42
Figure 2. Posterior, unweighted geometric means and 95% confidence intervals for the ratios of
juvenile to adult cancer potency for carcinogens acting primarily through a mutagenic
mode of action 43
Figure 3. Study designs 44
-------
PREFACE
U.S. Environmental Protection Agency (EPA or the Agency) cancer risk assessments
may be conducted differently than envisioned in this Supplemental Guidance for many reasons
including, for example, new information, new scientific understanding, or different science
policy judgment. The practice of risk assessment with respect to accounting for early-life
exposures to toxicants continues to develop, and specific components of this Supplemental
Guidance may become outdated or may otherwise require modification in individual settings. It
is EPA's intent to use, to the extent practicable and consistent with Agency statutes and
regulations, the best available science in its risk assessments and regulatory actions, and this
Supplemental Guidance is not intended to provide any substantive or procedural obstacle in
achieving that goal. Therefore, the Supplemental Guidance has no binding effect on EPA or on
any regulated entity. Where EPA does use the approaches in the Supplemental Guidance in
developing risk assessments, it will be because EPA has decided in the context of that risk
assessment that the approaches from the Supplemental Guidance are suitable and appropriate.
This judgment will be tested through peer review, and the risk assessment will be modified to
use different approaches if appropriate.
This Supplemental Guidance is intended for guidance only. It does not establish any
substantive "rules" under the Administrative Procedure Act or any other law and has no binding
effect on EPA or any regulated entity, but instead represents a non-binding statement of policy.
The Supplemental Guidance addresses a number of issues pertaining to cancer risks
associated with early-life exposures generally, but provides specific guidance on potency
adjustment only for carcinogens acting through a mutagenic mode of action. This guidance
recommends for such chemicals, a default approach using estimates from chronic studies (i.e.,
cancer slope factors) with appropriate modifications to address the potential for differential risk
of early-lifestage exposure. Default adjustment factors are meant to be used only when no
chemical-specific data are available to assess directly cancer susceptibility from early-life
exposure to a carcinogen acting through a mutagenic mode of action.
The Agency considered both the advantages and disadvantages of extending the
recommended, age dependent adjustment factors for carcinogenic potency to carcinogenic agents
for which the mode of action remains unknown. EPA recommends these factors only for
carcinogens acting through a mutagenic mode of action based on a combination of analysis of
available data and long-standing science policy positions that set out the Agency's overall
approach to carcinogen risk assessment, e.g., the use of a linear, no threshold extrapolation
procedure in the absence of data in order to be health protective. In general, the Agency prefers
VI
-------
to rely on analyses of data rather than on general defaults. When data are available for a
susceptible lifestage, they should be used directly to evaluate risks for that chemical and that
lifestage on a case-by-case basis. In the case of nonmutagenic carcinogens, when the mode of
action is unknown, the data were judged by EPA to be too limited and the modes of action too
diverse to use this as a category for which a general default adjustment factor approach can be
applied. In this situation per the Agency's Guidelines for Carcinogen Risk Assessment., a linear
low-dose extrapolation methodology is recommended. It is the Agency's long-standing science
policy position that use of the linear low-dose extrapolation approach (without further
adjustment) provides adequate public health conservatism in the absence of chemical-specific
data indicating differential early-life susceptibility or when the mode of action is not
mutagenicity.
The Agency expects to produce additional supplemental guidance for other modes of
action, as data from new research and toxicity testing indicate it is warranted. EPA intends to
focus its research, and to work collaboratively with its federal partners, to improve understanding
of the implications of early life exposure to carcinogens. Development of guidance for
estrogenic agents and chemicals acting through other processes resulting in endocrine disruption
and subsequent carcinogenesis, for example, might be a reasonable priority in light of the human
experience with diethylstilbesterol and the existing early-life animal studies. It is worth noting
that each mode of action for endocrine disruption will probably require separate analysis.
As the Agency examines additional carcinogenic agents, the age groupings may differ
from those recommended for assessing cancer risks from early-life exposure to chemicals with a
mutagenic mode of action. Puberty and its associated biological changes, for example, involve
many biological processes that could lead to changes in susceptibility to the effects of some
carcinogens, depending on their mode of action. The Agency is interested in identifying
lifestages that may be particularly sensitive or refractory for carcinogenesis, and believes that the
mode of action framework described in the Agency's Guidelines for Carcinogen Risk
Assessment is an appropriate mechanism for elucidating these lifestages. For each additional
mode of action evaluated, the various age groupings determined to be at differential risk may
differ from those described in this Supplemental Guidance. For example, the age groupings
selected for the age-dependent adjustments were initially selected based on the available data,
i.e., for the laboratory animal age range representative of birth to < 2 years in humans. More
limited data and information on human biology are being used to determine a science-informed
policy regarding 2 to < 16 years. Data were not available to refine the latter age group. If more
data become available regarding carcinogens with a mutagenic mode of action, consideration
may be given to further refinement of these age groups.
vn
-------
Access to data and other information relating to the Cancer Guidelines (U.S. EPA, 2005)
and this Supplemental Guidance will be through EPA's Risk Assessment Forum website, under
Publications, Guidelines, Guidelines for Cancer Risk Assessment. The URL is
http://www.epa.gov/cancerguidelines. The data and results of analyses are available in
spreadsheets.
Vlll
-------
1. INTRODUCTION
Cancer risk to children in the context of the U.S. Environmental Protection Agency's
cancer guidelines (U.S. EPA, 2005) includes both early-life exposures that may result in the
occurrence of cancer during childhood and early-life exposures that may contribute to cancers
later in life. The National Research Council (NRC, 1994) recommended that "EPA should
assess risks to infants and children whenever it appears that their risks might be greater than
those of adults." This document focuses on cancer risks from early-life exposure compared with
those from exposures occurring later in life. Evaluating childhood cancer and childhood
exposures resulting in cancer later in life are related, but separable, issues.
Historically, the focus on cancer has been as a disease associated with aging, resulting
from extended exposure duration with prolonged latency periods before the cancers appear.
Because much of cancer epidemiology addresses occupational exposures and because rodent
cancer studies are designed to last approximately a lifetime (two years) beginning after sexual
maturity, the cancer database used by EPA and other agencies for risk assessment focuses on
adults. However, extensive literature demonstrates that exposures early in life (i.e.,
transplacental or in utero, early postnatal, lactational) in animals can result in the development of
cancer (reviewed in Toth, 1968; Delia Porta and Terracini, 1969; Druckery, 1973; Rice, 1979;
Vesselinovitch et al., 1979; Rice and Ward, 1982; Vesselovitch et al., 1983; Anderson et al.,
2000). Thus, one element in extending analyses to children is to evaluate the extent to which
exposures early in life would alter the incidence of cancers observed later in life, compared with
the incidence observed with adult-only exposures (Anderson et al., 2000; NRC, 1993).
The causes of cancer encompass a variety of possible risk factors, including genetic
predisposition (Tomlinson et al., 1997), diet, lifestyle, associations with congenital
malformations (Bosland, 1996), and exposure to biological and physical agents and chemicals in
the environment. In some cases, tumors in adults and children have been compared (Anderson et
al., 2000; Ginsberg et al., 2002). Children and adults generally develop the same spectrum of
tumors when they have inherited gene and chromosomal mutations, such as Li-Fraumeni
syndrome (Birch et al., 1998). With ionizing radiation, which operates through a mutagenic
mode of action, both the young and the old develop many of the same tumors, with the
difference being that children are more susceptible for a number of tumor types (NRC, 1990;
U.S. EPA, 1994; UNSCEAR, 2000). Studies with anticancer drugs (cytotoxic and
immunosuppressive) demonstrate a similar spectrum of tumors (Hale et al., 1999; Kushner et al.,
1998; Larson et al., 1996; Nyandoto et al., 1998). Various viral infections, such as Epstein Barr
and hepatitis B, lead to lymphoma and liver cancer, respectively, in both age groups (Lindahl et
-------
al., 1974; Mahoney, 1999). These observations in humans indicate that the mode of action for
these agents would be the same or similar for adults and children.
Although there are similarities between childhood and adult tumors, significant
differences are also known to exist (Grufferman, 1998; Israel, 1995). Tumors of childhood
generally consist more of embryonic cell tumors, while adults have more carcinomas.
Leukemias, brain and other nervous system tumors, lymphomas (lymph node cancers), bone
cancers, soft tissue sarcomas, kidney cancers, eye cancers, and adrenal gland cancers are the
most common cancers of children, while skin, prostate, breast, lung, and colorectal cancers are
the most common in adults (Ries et al., 1999; U. S. Cancer Statistics Working Group, 2002).
Some tumors are unique to the young, including several with well established genetic bases, such
as tumors of the kidney (Wilms' tumor) or eye (retinoblastoma) (Anderson et al., 2000; Israel,
1995).
The relative rarity in the incidence of childhood cancers and a lack of animal testing
guidelines with perinatal1 exposure impede a full assessment of children's cancer risks from
exposure to chemicals in the environment. Unequivocal evidence of childhood cancer in humans
occurring from chemical exposures is limited (Anderson et al., 2000). Established risk factors
for the development of childhood cancer include radiation and certain pharmaceutical agents
used in chemotherapy (Reise, 1999). There is some evidence in humans for adult tumors
resulting from perinatal exposure. Pharmacological use of diethylstilbesterol (DES) during
pregnancy to prevent miscarriages induced clear cell adenocarcinoma of the vagina in a few
daughters exposed in utero though this tumor was not observed in exposed mothers (Hatch et al.,
1998; Robboy et al., 1984; Vessey, 1989). In addition to the limited human data, there are
examples of transplacental carcinogens in animal studies, such as recent studies with nickel and
arsenic (Diwan et al., 1992; Waalkes et al., 2003), as well as studies suggesting that altered
development can affect later susceptibility2 to cancer induced by exposure to other chemicals
(Anderson et al., 2000; Birnbaum and Fenton, 2003).
Infrequently, perinatal exposure in animals has been shown to induce tumors of different
types than those observed with adult exposures. Studies with saccharin (Cohen et al., 1995;
Whysner and Williams, 1996; IARC, 1999) and ascorbate (Cohen et al., 1998; Cohen et al.,
1995; NTP, 1983) found cancer when exposures were initiated in the perinatal period. In
1 Perinatal is defined as the time around birth and may include both prenatal (prior to birth) and postnatal
(afterbirth) periods.
2 Susceptibility is defined here as an increased likelihood of an adverse effect, often discussed in terms of
relationship to a factor that can be used to describe a human subpopulation (e.g., lifestage, demographic feature, or
genetic characteristic). The terms "susceptibility" and "sensitivity" are used with a variety of definitions in
published literature making it essential that readers are aware of these differences in terminology across documents.
-------
contrast, studies submitted to the Food and Drug Administration of approximately a dozen other
food additives and colorings that were not adult carcinogens did not indicate cancer, even when
perinatal exposures occurred (U.S. EPA, 1996). When observed, the differences between
childhood and adult cancers suggest the importance of evaluating the impacts of maternal
exposures during pregnancy as well as exposures to children (Anderson et al., 2000). The effects
of maternal exposures and transplacental carcinogens require separate evaluation and are not
quantitatively evaluated in the analysis presented below.
The limited human information described briefly above is supported by a number of
animal bioassays that include both perinatal and adult exposures to chemicals. Standard animal
bioassays generally begin dosing after the animals are 6-8 weeks old, when many organs and
systems are almost fully developed, though substantial growth in body size continues thereafter
(as more fully discussed in Hattis et al., 2005). The literature can be divided roughly into three
types of exposure scenarios: those that include repeated exposures for the early postnatal to
juvenile period, as compared with chronic later-life dosing; lifetime (i.e., combined perinatal and
adult) exposure as compared with chronic later-life dosing; and those that include more acute
exposures, such as a single intraperitoneal (ip) or subcutaneous injection, for both early-life and
later-life dosing. In the early-life exposure studies that are available, perinatal exposure usually
induces higher incidence of tumors later in life than the incidence seen in standard bioassays
where adult animals only were exposed; some examples include diethylnitrosamine (DEN) (Peto
et al., 1984), benzidine (Vesselinovitch et al., 1979), DDT (Vesselinovitch et al., 1979), and
polybrominated biphenyls (PCBs) (Chhabra et al., 1993a). Reviews comparing early-life
carcinogenesis bioassays with standard bioassays for a limited number of chemicals (McConnell,
1992; Miller et al., 2002; U.S. EPA, 1996) have concluded:
• The same tumor sites usually are observed following either perinatal or adult exposure.
• Perinatal exposure in conjunction with adult exposure usually increases the incidence of
tumor bearing animals or reduces the latent period before tumors are observed.
There is limited evidence to inform the mode(s) of action leading to differences in tumor
type and tumor incidence following early-life exposure and exposure later in life. Differences in
the capacity to metabolize and clear chemicals at different ages can result in larger or smaller
internal doses of the active agent(s), either increasing or decreasing risk (Ginsberg et al., 2002;
Renwick, 1998). There is reason to surmise that some chemicals with a mutagenic mode of
action, which would be expected to cause irreversible changes to DNA, would exhibit a greater
effect in early-life versus later-life exposure. Several studies have shown increased susceptibility
-------
of weanling animals to the formation of DNA adducts following exposure to vinyl chloride (Laib
et al., 1989; Morinello et al., 2002a; Morinello et al., 2002b). Additionally, even though not used
quantitatively in the analyses in this document, a recent analysis of in vivo transplacental
micronucleus assays indicated that fetal tissues generally are more sensitive than maternal tissues
for induction of micronuclei from mutagenic chemicals (Hayashi et al., 2000), providing
qualitative support for the early-life susceptibility. Similarly, the neonatal mouse model for
carcinogenesis, which uses two doses prior to weaning followed by observation of tumors at one
year, shows carcinogenic responses for mutagenic agents (Flammang et al., 1997; McClain et al.,
2001). These results are consistent with the current understanding of biological processes
involved in carcinogenesis, which leads to a reasonable expectation that children can be more
susceptible to carcinogenic agents than adults (Anderson et al., 2000; Birnbaum and Fenton,
2003; Ginsberg, 2003; Miller et al., 2002; Scheuplein et al., 2002). Some aspects potentially
leading to childhood susceptibility include the following issues.
• More frequent cell division during development can result in enhanced fixation of
mutations due to the reduced time available for repair of DNA lesions and clonal
expansion of mutant cells gives a larger population of mutants (Slikker et al, 2004).
• Some embryonic cells, such as brain cells, lack key DNA repair enzymes.
• Some components of the immune system are not fully functional during development
(Holladay and Smialowicz, 2000; Holsapple et al., 2003).
• Hormonal systems operate at different levels during different lifestages (Anderson et al.,
2000).
• Induction of developmental abnormalities can result in a predisposition to carcinogenic
effects later in life (Anderson et al., 2000; Birnbaum and Fenton, 2003; Fenton and
Davis, 2002).
The methodology that has been generally used by the U.S. EPA to estimate cancer risk
associated with oral exposures relies on estimation of the lifetime average daily dose, which can
account for differences between adults and children with respect to exposure factors such as
eating habits and body weight. However, susceptibility differences with respect to early
lifestages are not taken into consideration because cancer slope factors3 are based upon effects
3 Cancer slope factor - An upper bound estimate of the increased cancer risk from a lifetime exposure to an
agent. This estimate, usually expressed in units of proportion (of a population) affected per unit exposure (e.g.,
mg/kg-day or ug/m3), is generally reserved for use in the low-dose region of the dose-response relationship. It is
often the statistical upper bound on the potency and therefore the risk. "Upper bound" in this context is a plausible
-------
observed following exposures to adult humans or sexually mature animals. Since a much larger
database exists for chemicals inducing cancer in adult humans or sexually mature animals, it is
necessary to determine whether adjustment of such adult-based cancer slope factors would be
appropriate when assessing cancer risks associated with exposures early in life. The analysis
undertaken here addresses this issue, focusing upon studies that define the potential duration and
degree of increased susceptibility that may arise from childhood, defined as early-life (typically
postnatal and juvenile animal) exposures. Some of these analyses, along with a more complete
description of the procedures used, have been published (Barton et al., 2005). The analysis
presented in this Supplemental Guidance and in the published article form the basis for
developing Supplemental Guidance for evaluating cancer susceptibility associated with early-life
exposures.
upper limit to the true probability.
-------
2. PROCEDURES
This section describes the steps taken to assess potential susceptibility to early-life
exposure to carcinogenic compounds compared with adult and whole-life exposure. The readily
available literature was reviewed to identify animal studies that compared tumor incidence
between early-life and adult-only exposures or between early-life-and-adult and adult-only
exposures. Studies were categorized by length of exposure; those studies with quantitative
information to estimate tumor incidence over time for early-life and adult exposures were
identified. These studies provided the basis for quantitatively estimating the difference in
susceptibility between early-life and adult exposures, as described below. Finally, summaries of
available human data for radiation exposure were reviewed in the context of tumor incidence
from early-life versus later-in-life exposure.
2.1. DATA SOURCES FOR ANIMAL STUDIES
Studies in the literature included in this analysis are those that report tumor response from
experiments that included both early-life and adult exposure as separate experimental groups.
Initial studies for consideration were identified through review articles and a search of the
National Toxicology Program (NTP) database. Reviews of the literature regarding cancer
susceptibility from early-life exposure in animals include McConnell (1992), Ginsberg (2003),
Anderson et al. (2000), Miller et al. (2002) and U.S. EPA (1996). A literature search was
conducted utilizing key words and MeSH headings (Medline) from studies identified in the
available reviews. The list of chemicals included in this analysis for quantitative evaluation is
shown in Table la and Ib.
Abstracts or papers were reviewed to determine if a study provided information that
could be used for quantitative analysis. The criteria used to decide if a study could be included
in the quantitative analysis were:
• Exposure groups at different post-natal ages in the same study or same laboratory, if not
concurrent (to control for a large number of potential cross-laboratory experimental
variables including pathological examinations),
• Same strain/species (to eliminate strain-specific responses confounding age-dependent
responses),
• Approximately the same dose within the limits of diets and drinking water intakes that
obviously can vary with age (to eliminate dose-dependent responses confounding age-
dependent responses),
-------
• Similar latency period following exposures of different ages (to control for confounding
latency period for tumor expression with age-dependent responses), arising from sacrifice
at >1 year for all groups exposed at different ages, where early-life exposure can occur up
to about 7 weeks. Variations of around 10 to 20% in latency period are acceptable,
• Postnatal exposure for juvenile rats and mice at ages younger than the standard 6 to 8
week start for bioassays; prenatal (in utero) exposures are not part of the current analysis.
Studies that have postnatal exposure were included (without adjustment) even if they also
involved prenatal exposure,
• "Adult" rats and mice exposure beginning at approximately 6 to 8 weeks old or older, i.e.
comparable to the age at initiation of a standard cancer bioassay (McConnell, 1992).
Studies with animals only at young ages do not provide appropriate comparisons to
evaluate age-dependency of response (e.g., the many neonatal mouse cancer studies).
Studies in other species were used a supporting evidence, because they are relatively rare
and the determination of the appropriate comparison ages across species is not simple,
and
• Number of affected animals and total number of animals examined are available or
reasonably reconstructed for control, young, and adult groups (i.e., studies reporting only
percent response or not including a control group would be excluded unless a reasonable
estimate of historical background for the strain was obtainable).
Tables 2 and 3 include information on the methods and results from the animal studies
identified in Table Ib. Pertinent information on species, sex, dosing regimen, and tumor
incidence is given. Additionally, the "Notes" column includes general information about the
relationship between tumor incidence, animal age at first dosing, and sex. The data in Tables 2
and 3 were used for the calculations, described below, for estimating potentially increased cancer
risk from early-life exposure.
The available literature includes a wide range of exposure scenarios. This range is due in
part to the lack of a defined protocol for early-life testing and the difficulty of standardizing and
administering doses preweaning. As noted previously, the literature can be divided roughly into
three types of exposure scenarios: those that include repeated exposures for the early postnatal to
juvenile period, as compared with chronic later-life dosing; lifetime (i.e., combined perinatal and
adult) exposure as compared with chronic later-life dosing; and those that include more acute
exposures, such as a single intraperitoneal (ip) or subcutaneous injection, for both early-life and
later-life dosing. Table 2 includes the studies that had early postnatal to juvenile exposures, adult
chronic exposures, and lifetime exposures. Table 3 includes studies with acute exposures. A
discussion of the implications of the different exposure scenarios is included in Section 3.
-------
Studies were identified for more than 50 chemicals not included in Tables 2 and 3 that
demonstrated carcinogenesis following perinatal exposure, but did not directly compare
exposures at different ages. A large number of studies address in utero exposures only. More
than 100 chemicals (with both negative and positive findings) have been studied in the neonatal
mouse assay, but this assay does not have a comparable adult exposure (Flammang et al., 1997;
McClain et al., 2001; Fujii, 1991). Studies across laboratories often varied in their use of animal
strains (e.g., for AZT studies, Diwan et al., 1999 used CD-I mice, while NTP, 1999 used
B6C3Fi mice). Studies of tamoxifen use two Wistar-derived strains and had very different
periods for tumor expression, i.e., sacrifice at 20 months for adult-exposed rats and natural death
up to 35 months for juvenile-exposed rats, with uterine tumors observed in animals dying after
22 months (Carthew et al., 2000; Carthew et al., 1996; Carthew et al., 1995). Due to these
factors, the chemicals that belong to this group were not evaluated quantitatively. In addition,
there were studies assessing radiation in animals (Covelli et al., 1984; Di et al., 1990; Sasaki et
al., 1978). The radiation data were not analyzed in depth, in part because there are recognized
differences in toxicokinetics and toxicodynamics between radiation and chemicals with a
mutagenic mode of action for carcinogenesis. Even though the data on A-bomb survivors
provide information for many different cancer sites in humans with a single exposure involving
all ages, a number of national and international committees of experts have analyzed and
modeled these data to develop risk estimates for various specific applications. Furthermore, lack
of uniformity regarding radiation doses, gestational age at exposure, and the animal strains used
make it difficult to make comparisons across studies (Preston et al., 2000).
2.2. EVALUATING THE MODE OF ACTION OF CARCINOGENS
Evaluation of the mode of action of a carcinogen was based upon a weight-of-evidence
approach. Multiple modes of action are associated with the chemicals in this database, but a
number are associated with mutagenicity (i.e., benzo(a)pyrene, benzidine, dibenzanthracene,
diethylnitrosamine, dimethylbenz(a)anthracene, dimethylnitrosamine, ethylnitrosourea, 3-
methylcholanthrene, methylnitrosourea, safrole, urethane, and vinyl chloride). Determination of
carcinogens that are operating by a mutagenic mode of action entails evaluation of short-term
testing results for genetic endpoints, metabolic profiles, physicochemical properties, and
structure-activity relationship (SAR) analyses in a weight-of-evidence approach (Dearfield et al.,
1991; U.S. EPA, 1986, 1991; Waters et al., 1999), as has been done for several chemicals (e.g.,
Dearfield et al., 1999; McCarroll et al., 2002; U.S. EPA, 2000a). Key data for a mutagenic mode
of action may be evidence that the carcinogen or a metabolite is DNA reactive and/or has the
ability to bind to DNA. Also, such carcinogens usually produce positive effects in multiple test
-------
systems for different genetic endpoints, particularly gene mutations and structural chromosome
aberrations, and in tests performed in vivo which generally are supported by positive tests in
vitro. Additionally, carcinogens may be identified as operating via a mutagenic mode of action
if they have similar properties and SAR to established mutagenic mode of action.
2.3. QUANTITATIVE METHODS
To estimate the potential difference in susceptibility between early-life and adult
exposure, we calculated the estimated ratio of the cancer potency from early-life exposure
compared to the estimated cancer potency from adult exposure. The cancer potency was
estimated from a one-hit model, or a restricted form of the Weibull model, which is commonly
used to estimate cumulative incidence for tumor onset. The general form of the equation is:
P(dose) = l-[l-P(0)]exp(-cancer potency *dose)
The ratio of juvenile to adult cancer potencies were calculated by fitting this model to the
data for each age group. The model fit depended upon the design of the experiment that
generated the data. Two designs should be handled separately: experiments in which animals are
exposed either as juveniles or as adults (with either a single or multiple dose in each period), and
experiments in which exposure begins either in the juvenile or in the adult period, but once
begun, continues through life.
For the first case, the model equations are:
where:
subscripts A and /refer to the adult and juvenile period, respectively,
X is the natural logarithm of the juvenile: adult cancer potency ratio,
PO is the fraction of control animals with the particular tumor type being modeled,
Px is the fraction of animals exposed in age period x with the tumor,
MA is the rate of accumulation of "hits" per unit of time for adults, i.e., the cancer
potency, and
Sx is the duration or number of exposures during age period x.
For a substantial number of data sets (acute exposures), dj = SA = 1. We are interested in
-------
determining X, which is the logarithm of the estimated ratio of juvenile to adult cancer potencies,
a measure of potential susceptibility for early-life exposure.
For the second kind of design, the model equations should take into account that
exposures that were initiated in the juvenile period continue through the adult period. The model
equations for the fraction of animals exposed only as adults with tumors in this design are the
same as in the first design, but the fraction of animals whose first exposure occurred in the
juvenile period is:
(2)
All symbols in (eq. 2) have the same interpretation as their counterparts in (eq. 1), but
now dj includes the duration of exposure during the juvenile period as well as the subsequent
adult period.
Parameters in these models were estimated using Bayesian methods (see, for example,
Carlin and Louis, 2000), and all inferences about the ratios were based on the marginal posterior
distribution of X. Some of these analyses, including a more complete description of the
procedures (including the potential effect of alternative Bayesian priors that have been
examined) have been published (Barton et al., 2005). The data for estimating each ratio were in
the form of numbers of animals tested and number affected for each of control, juvenile-exposed,
and adult-exposed animals, and duration of exposure for each of the juvenile-exposed and adult-
exposed groups. A few data sets had separate control groups for the juvenile-exposed and adult-
exposed groups, and equations 1 and 2 were modified accordingly. The likelihood for the
parameters in the model was the product of three (or four, if there were two control groups)
binomial probabilities: for the number of animals with tumors in the control group(s), for the
juvenile-exposed group, and for the adult-exposed group. The prior for P0 (the fraction of
control animals with a particular tumor) was right triangular (right angle at the origin), based on
the assumption that control incidences should be relatively low. (The base of the distribution is
one, as PO can not exceed one. As this is a probability distribution, the area of the triangle is one.
Therefore, its height at the origin must be 2.) The effect of exposure in adults is quantified by
the extra risk, Q, where the probability that an animal has a tumor is Po+(l -Po)Q- So, from
equations 1, Q = l- e~mA , Q was given a uniform prior on the interval (0,1), reflecting total
ignorance about the extra risk of adult exposure. Finally, the prior for X was Gaussian with mean
0 (corresponding to a median or geometric mean ratio of one) and standard deviation 3. The
prior for the log ratio of juvenile to adult cancer potency has some influence over the posterior
estimates for the ratio of juvenile to adult potency. The magnitude of that influence depends on
10
-------
the amount of support in the data for different values of the log ratio. The prior also effectively
downweights extremely large or small values for the juvenile to adult potency ratio. Three priors
for the standard deviation were evaluated (Barton et al., 2005, see Appendix), with the intent of
finding the largest prior, i.e., one that would contain the least informative assumption for the
prior. A standard deviation of 9 was tried, but some of the intervals would not converge. A
standard deviation of 3 worked well, allowed ratio estimates to be derived, with all of the data of
interest. An intermediate value of 6 was also examined to ascertain if a less informative prior
could be used. While the intervals converged, a sensitivity analysis showed that this value for the
standard deviation resulted in sufficient down-weighting of the ratios with limited information
that these data would not influence the result. This was considered an unreasonable bias, so a
standard deviation of 3 was used for the further analyses. A further discussion of these analyses
can be found in Barton et al. (2005).
The posterior distribution for the unknown parameters in these models is the product of
the likelihood from the data and the priors (the "unnormalized" prior), divided by a
normalization constant that is the integral of the unnormalized prior over the ranges of all the
parameters. This normalization constant was computed using numerical integration, as were
posterior means and variances and marginal posterior quantiles for the log-ratio X. All numerical
computations were carried out in the R statistical programming language (version 1.8.1; R
Development Core Team, 2003).
This method produced a posterior mean ratio of the early-life to adult cancer potency,
which is an estimate of the potential susceptibility of early-life exposure to carcinogens. If the
ratio was greater than one, this indicated that the experiment found that there was greater
susceptibility from early-life exposure. If the ratio was less than one, this indicated that the
experiment found that there was less susceptibility from early-life exposure. Summaries of the
individual ratios from each of the dose groups from the different experiments for different
groupings were also calculated (for example for all acute exposures of chemicals that are
carcinogenic by a mutagenic mode of action). The summary ratios were constructed from the
individual ratios within a group, by variance-weighting the means of each ratio. The individual,
posterior means were weighted by using reciprocals of their posterior variance. This weighting
procedure is commonly used because it gives greater weight to those studies for which the
variances, i.e., the uncertainties, are smaller. Because the ratios were calculated as log ratios (see
eq. 1), exponentiating the resulting inverse-variance-weighted mean yielded inverse-variance-
weighted geometric means of ratios.
11
-------
2.4. IONIZING RADIATION
A supporting role was assigned to the available human radiation data, where cancer
incidence in adults who were children at the time of the atomic bomb (A-bomb) exposure was
compared with cancer incidence in adults who were older at the time of exposure. Although there
are recognized differences in toxicokinetics and toxicodynamics between radiation and chemical
carcinogens with a mutagenic mode of action, the data on A-bomb survivors provide information
for many different cancer sites in humans with a single exposure involving all ages. In addition
to the richness of the data, a number of national and international committees of experts have
analyzed and modeled these data to develop risk estimates for various specific applications.
The report of the United Nations Scientific Committee on the Effects of Atomic
Radiation (UNSCEAR, 2000, with Scientific Annexes) lists more than 80 studies, in addition to
the reports of the Japanese A-bomb survivors, in which at least one type of cancer was measured
in humans who were exposed either intentionally or accidentally to some form of ionizing
radiation. However only the A-bomb survivor reports have relevant information on incidence of
early-life exposures. One of the more recent papers cited in the UNSCEAR report, by Thompson
et al. (1994), contains detailed data on the incidence of 21 different cancers in 37,270 exposed A-
bomb survivors (42,702 unexposed). Also, EPA has used data from the A-bomb survivors to
develop age-specific relative risk coefficients using various methods for transporting the risk
from the Japanese population to the U.S. population (U.S. EPA, 1994). It is beyond the scope of
this effort to present all of the radiation data or a discussion of the various analyses and modeling
efforts. Rather, information relevant to comparing cancer risks from juvenile versus adult
exposure from UNSCEAR (2000) and U.S. EPA (1994; 1999) is presented as representative
findings to determine whether the radiation data are similar qualitatively to the chemical
findings. More detailed data on the A-bomb survivors can be found in Delongchamp et al.
(1997) and Preston et al. (2000).
As previously noted, several studies have assessed radiation in animal studies (Covelli et
al., 1984; Di et al., 1990; Sasaki et al., 1978). However, lack of uniformity regarding radiation
doses, gestational age at exposure, and the animal strains used make it difficult to compare the
experimental data on cancer induction after prenatal irradiation (Preston et al., 2000).
12
-------
3. RESULTS
3.1. QUALITATIVE EVALUATION OF THE DATABASE
The question addressed in this analysis was whether, and how, available quantitative
scientific data could inform risk assessment policy choices for adjusting cancer slope factors
when they are used in the assessment of cancer risk from childhood exposure. Cancer slope
factors are, with few exceptions, based on adult human epidemiology or standard chronic adult
rodent bioassays, which do not address the impacts of early-life exposures. Thus, the critical
data are either human epidemiological data on childhood exposures resulting in adult cancer or
research studies with rodents involving early postnatal exposures. The major human data
available are from radiation exposures (studies summarized in Tables 9-11), with very limited
data available for humans exposed during childhood to chemicals (reviewed in Anderson et al.,
2000; Miller et al., 2002).
A review of the literature identified several hundred references reporting more than 50
chemicals that have been shown to be able to cause cancer following perinatal exposure (Table
la) (reviewed in Toth, 1968; Delia Porta and Terracini, 1969; Druckery, 1973, Rice, 1979;
Vesselinovitch et al., 1979; Rice and Ward, 1982; Vesselovitch et al.; 1983; Fujii, 1991;
Anderson et al., 2000). Studies (or groups of studies from a single laboratory on a given
chemical) that directly provided quantitative data on carcinogenesis following early postnatal
exposures and adult exposures to chemicals in animals were identified for 18 chemicals, listed in
Table Ib, 2, and 3. Of the identified studies, there were 11 chemicals involving repeated
exposures during early postnatal and adult lifestages (Table Ib) and 8 chemicals using acute
exposures (typically single doses) at different ages (Table Ib). Some of the studies evaluated
single tissues or organs for tumors (e.g., only liver), while others evaluated multiple tissues and
organs (Tables 2 and 3). Mice, rats, or both species and sometimes multiple strains were tested.
These studies serve as the basis for the quantitative analyses presented later in the results.
In addition to the studies identified in Table Ib, studies were identified with early
postnatal and early-life exposures that were evaluated qualitatively but not quantitatively. Some
of these studies are notable and provide important supporting information. Two recent studies
used transgenic mouse models for human tumors. Increased multiplicity of colon tumors was
observed following earlier versus later azoxymethane exposures (Paulsen et al., 2003).
Shortened mammary tumor latency following estradiol exposure occurred when exposures
occurred between 8 and 18 weeks as opposed to earlier or later, which is generally consistent
with the incidence results analyzed for DMBA (Yang et al., 2003). Several notable examples
exist of developmental windows leading to cancer susceptibilities that were not observable in
13
-------
adults. Several potent estrogenic chemicals including DBS, tamoxifen, and genistein produce
uterine tumors with early postnatal exposures of mice, though there also appear to be strain-
dependent differences in the tumor sites in adult mice (Gass et al., 1964; Greenman et al., 1990;
Newbold et al., 1990, 1997, 1998, 2001). Developmental susceptibilities are believed to play a
key role in effects observed with saccharin (Cohen et al., 1995; Whysner and Williams, 1996)
and ascorbate (Cohen et al., 1998; NTP, 1983), with bladder tumors arising when early-life
exposures occurred. Studies with several species, including rat, mouse, and opossum, indicate
that nervous systems tumors associated with exposures to ENU and several other chemicals
appear to be highly dependent upon exposures occurring within certain windows, particularly
prenatal ones (Rice, 1979; Rice and Ward, 1982; Jurgelski et al., 1979).
Analyses of the difference in cancer risk from exposures during different lifetime periods
ideally should address both the period of potential susceptibility and the magnitude of the
susceptibility. Available studies used a variety of study designs (see Tables 2 and 3), which can
be valuable because they provide different information (Figure 1). However, variations in study
design can result in a lack of comparability across chemicals, and can limit information on the
consistency of effects with different chemicals acting through different modes of action. The
acute dosing (largely single dose) studies (Table 3) are valuable because they involve identical
exposures with explicitly defined doses and time periods demonstrating that differential tumor
incidences arise exclusively from age-dependent susceptibility. These studies address both the
period and magnitude of susceptibility. They were not as appropriate for quantitative
adjustments for the cancer potency estimates because of their limitations, including that most
used subcutaneous or ip injection that historically have not been considered quantitatively
relevant routes of environmental exposure for human cancer risk assessment by EPA, and that
these routes of exposure are expected to have only partial or a complete absence of first pass
metabolism that is likely to affect potency estimates.
The repeated dosing studies with exposures during early postnatal or adult lifetime
provide useful information on the relative impact of repeated exposures at different lifestages
and may be more likely to have exposure occur during a window of susceptibility, if there is one.
One notable difference in study designs was that studies with repeated early postnatal exposure
were included in the analysis even if they also involved earlier maternal and/or prenatal
exposure, while studies addressing only prenatal exposure were not otherwise a part of this
analysis. Another notable difference among studies involved the tissues that were evaluated for
tumors: some studies focused on a single tissue, particularly liver, while others evaluated
multiple tissues.
Comparisons within a single repeated dosing study may have limitations for evaluating
14
-------
differential susceptibility because exposures to the chemical can differ during the different
lifestages, particularly when dietary or drinking water exposures are involved. A notable
example is the PCB study (Chhabra et al., 1993a), in which mobilization of such lipid-soluble
chemicals into mother's milk would be expected to result in infants receiving much larger
exposures than other lifestages. While lactational transfer is just as relevant to human nursing
offspring, this difference in exposure obscures the extent to which the early lifestage is
quantitatively more susceptible (i.e., part of the increased early-life cancer risk arises from higher
exposure than during the adult period). Maternal metabolism of compounds such as
diphenylhydantoin (DPH) (Chhabra et al., 1993b) also may result in lower exposure during
lactation, potentially underestimating the early-lifestage risk, if the parent compound is the active
form of the chemical. Similar issues exist due to normal age-dependent changes in food and
water consumption. Ascribing differential effects observed in animal studies solely to lifestage
susceptibility must be done carefully as there may also be differences in the exposures. There
are substantial and clear benefits, therefore, from experimental consistency when comparisons
are made directly within a study (e.g., same species and strain, consistent pathological
evaluation).
One issue to note is the rationale for the organization of the available data. It was
observed that the results across a broad range of chemicals with a variety of modes of action
were somewhat variable. Therefore, consistent with the approach of the EPA cancer guidelines
(U.S. EPA, 2005), an approach based on mode of action appeared to be a common framework
for analysis. Variability in lifestage-dependent susceptibility and susceptibility across a range of
modes of action was further supported by theoretical analyses using multistage and two-stage
models of carcinogenesis (Goddard and Krewski, 1995; Murdoch et al., 1992).
3.2. QUANTITATIVE EVALUATION OF THE DATABASE
As described in the Section 2.3, the potential difference in susceptibility between early-
life and adult exposure was calculated as the estimated ratio of cancer potency from early-life
exposure over the cancer potency from adult exposure. Tables 4-7 present the results of the
quantitative analysis using the studies that were determined qualitatively to have appropriate
study designs (Tables 2 and 3) containing sufficient information to analyze. Based on the studies
available, the calculations were organized into four tables: (1) compounds acting through a
primarily mutagenic mode of action, where the compound was administered by a chronic dosing
regimen to adults and repeated dosing in the early postnatal period (Table 4); (2) compounds
acting through a primarily nonmutagenic mode of action, where the compound was administered
by a chronic dosing regimen to adults and repeated dosing in the early postnatal period (Table 5);
15
-------
(3) compounds acting through a primarily mutagenic mode of action, where the compounds were
administered by an acute dosing regimen (Table 6); and (4) compounds acting primarily through
either a mutagenic or nonmutagenic mode of action with chronic adult dosing and repeated early
postnatal dosing (Table 7). In these tables, the 2.5% and 97.5% are percentiles of the posterior
distribution. For a Bayesian distribution, these percentiles function in a manner similar to the
95% confidence limits for other types of statistical analyses. The results are discussed below,
followed by a description of results from analyses of studies of humans exposed to radiation.
3.2.1. Carcinogens with a Mutagenic Mode of Action
The most informative database on early-lifestage susceptibility exists for chemicals with
a well-accepted mutagenic mode of action (e.g., diethylnitrosamine, vinyl chloride). This
database includes both single-dose studies and repeated-dose studies involving periods of
postnatal and/or chronic exposure. These studies help define the periods of increased
vulnerability and the magnitude of the susceptibility. The acute dosing studies demonstrate that
the age-dependent responses are not due to differences in exposure, because these studies
explicitly control the exposure.
3.2.1.1. Early Postnatal, Juvenile, and Adult Repeated Dosing Studies of Chemicals with a
Mutagenic Mode of Action
Studies comparing repeated dosing for early-life, adult, or lifetime exposures exist for six
carcinogens with a mutagenic mode of action [benzidine, diethylnitrosamine (DEN), 3-
methylcholanthrene, safrole, urethane, and vinyl chloride]; DEN also had acute dosing studies.
Lifetime (i.e., combined juvenile and adult) compared to adult exposure studies were analyzed
for DEN, safrole, and urethane, while studies comparing juvenile with adult exposures were
analyzed for benzidine, 3-methylcholanthrene, safrole, and vinyl chloride. These chemicals all
require metabolic activation to the active carcinogenic form. Analysis of the tumors arising per
unit time of exposure found that juvenile exposures with each chemical could be more effective
than adult exposures were at inducing tumors (Tables 4 and 7; Figure 2, a graphic representation
of the posterior, unweighted geometric means and their 95% confidence intervals, for the ratios
of juvenile to adult cancer potency for carcinogens acting through a mutagenic mode of action).
The weighted geometric mean for repeat and lifetime exposures is 10.4; for acute exposures the
weighted geometric mean value is 1.5. For benzidine and safrole, there was a notable sex
difference, with high liver tumor incidence observed for early postnatal exposures of male, but
not female, mice. For both the acute and the repeated/lifetime data, the 95th percentile of the
individual, unweighted geometric means is above 10 (Figure 2).
16
-------
This analysis focused upon the duration of exposure as a surrogate for dose, essentially
assuming that the doses animals received during the different periods of these studies were
similar. This assumption is a limitation of the analysis because these studies involved exposures
via lactation (i.e., dosing the mother prior to weaning), drinking water, diet, or inhalation, which
have the potential to deliver different doses at different lifestages. However, the range of the
magnitudes of the tumor incidence ratios of juvenile to adult exposures is similar (Table 8) for
the repeated dosing studies (0.12-111, weighted geometric mean 10.5, 42% of ratios greater
than 1), lifetime dosing studies (0.18 - 79, weighted geometric mean 8.7, 67% of ratios greater
than 1), and acute dosing studies (0.01 - 178, weighted geometric mean 1.5, 55% of ratios
greater than 1), suggesting that these differences in dosing are not the sole determinant of the
increased incidence of early tumors, i.e., uncertainty and variability remain. Because these
comparisons include different chemicals with different tissue specificities, it may be informative
to consider liver as a target organ affected by all of these chemicals. The range of the
magnitudes of the liver tumor incidence ratios of juvenile to adult exposures is similar for the
repeated dosing studies (0.12 - 111, weighted geometric mean 41.8, 86% of ratios greater than 1,
Table 4), lifetime dosing studies (0.47 - 79, weighted geometric mean 14.9, 80% of ratios greater
than 1, Table 7), and acute dosing studies (0.1 - 40, weighted geometric mean 8.1, 77% of ratios
greater than 1, Table 8). Thus, the repeated dose studies support the concept that early-lifestage
exposure to carcinogenic chemicals with a mutagenic mode of action would lead to an increased
tumor incidence compared with adult exposures of a similar duration and dose.
3.2.1.2. Acute Dosing Studies of Chemicals with a Mutagenic Mode of Action
Acute dosing studies are available for eight carcinogens with a mutagenic mode of action
that were administered to mice or rats [benzo[a]pyrene (BaP), dibenzanthracene (DBA),
Diethylnitrosamine (DEN), dimethylbenzanthracene (DMBA), dimethylnitrosamine (DMN),
ethylnitrosourea (ENU), methylnitrosourea (NMU), and urethane (also known as ethyl
carbamate)] (Table Ib). Except for ENU and NMU, these compounds require metabolic
activation to their active carcinogenic forms. These acute dosing studies generally compared a
single exposure during the first few weeks of life with the identical or similar exposure in young
adult animals (Tables 3 and 6). Many of these studies compared exposures during the
preweaning period (i.e., approximately day 21 for rats and mice) with effects around week 6,
which is approximately the age at which typical chronic bioassays begin dosing animals. These
studies largely were by subcutaneous or ip injection, which historically have not been considered
quantitatively relevant routes of environmental exposure for human cancer risk assessment by
EPA. For purposes of comparing age-dependent susceptibilities to tumor development, these
17
-------
data are highly relevant. The injection route typically alters the pharmacokinetic time courses of
the parent compound and the metabolites compared with oral or other exposures due to altered
kinetics of absorption and metabolism. However, for these compounds and the systemic organ
effects observed, there are several pharmacokinetic reasons to believe that the age-dependent
trends would be similar with other routes of exposure. These compounds are expected to be
reasonably well absorbed orally, comparable with injection routes, and largely require metabolic
activation, so partial or complete absence of first pass metabolism in the injection studies would
be similar to or underestimate metabolic activation when compared with oral exposure.
The early exposures often resulted in higher incidence of tumors than later exposures,
with increased early susceptibilities up to 178-fold (unweighted ratios in Table 6 range from
0.011 to 178, with a weighted geometric mean of 1.5, and 55% of ratios greater than 1, Figure 2,
Table 8). Examples of the general age-dependent decline in susceptibility of tumor response
include BaP (liver tumors), DEN (liver tumors), ENU (liver and nervous system tumors), and
urethane (liver and lung tumors). While generally the Day 1 and Day 15 time points were higher
than later time points, in several cases similar tumor incidence was observed at both these early
times (e.g., ENU-induced kidney tumors, Tables 6 and 8).
While the degree of susceptibility generally declines during the early postnatal period
through puberty into early adulthood, there are exceptions due perhaps to pubertal periods of
tissue development (e.g., mammary tissues) or very early development of xenobiotic
metabolizing enzymes. One such exception was the increased incidence of mammary tumors in
5-8 week old rats given DMBA, compared with older or younger rats (Meranze et al., 1969;
Russo et al., 1979). Meranze et al. (1969) reported 8% mammary tumors following a single dose
of DMBA at less than two weeks, 56% if given once to animals between 5 and 8 weeks old, and
15% when given once to 26 week old rats. Thus, a ratio of 7.1 is obtained when comparing
susceptibilities of 5-8 week and 26-week-old rats (Table 6) compared to a ratio of 0.2 when
comparing the exposure at 2 weeks versus 26 weeks. A similar effect was observed by Russo et
al. (1979); see Table 3. This observation corresponds well with pubertal development of the
mammary tissue, with ovarian function commencing between 3 and 4 weeks (after the < 2 week
time point in the Meranze et al., 1969 study), and mammary ductal growth and branching
occurring such that it is approximately two-thirds complete by week 5, consistent with the 5-8
week susceptible period of Meranze et al. (Silberstein, 2001). While this differs from the general
trend previously discussed, it indicates susceptibility later in the juvenile period rather than
earlier. Another example of deviation from the general trend toward an age-dependent decline is
DEN-induced lung tumors that were somewhat lower in incidence following exposure on day 1
than observed for the day 15 or day 42 exposures (Vesselinovitch et al., 1975) (Tables 3 and 6).
18
-------
There are substantial differences in the early-life susceptibility of different tissues observed in
the acute studies (Table 8). It should be noted that the target tissues vary with chemical, so the
number of chemicals for which data are available varies for each tissue. Several tissues have
weighted geometric mean ratios of greater than 1 including kidney, leukemia, liver, lymph,
mammary, nerve, reticular tissue, thymic lymphoma, and uterus/vagina. Some of these, such as
the nerve and mammary tumors, appear to have a very specific window of susceptibility, as
noted above, and the ratios were much higher if the exposure occurred during this window.
Tissues with weighted mean ratios less than 1 include forestomach, harderian gland, ovaries, and
thyroid. Lung has a weighted geometric mean of 1. Many of the studies produced very high
lung tumor responses regardless of age, so the results are difficult to interpret, as illustrated by
the dose-response data with urethane in Rogers (1951) in which the increased early susceptibility
is only apparent when the dose is low. The large numbers of studies with high lung tumor
responses at all ages contribute to the differences in the weighted geometric means for the acute
and for the repeated dosing studies.
Overall, the acute dosing studies support the concept that early-lifestage exposure to
carcinogenic chemicals with a mutagenic mode of action would lead to an increased incidence of
tumors compared with adult exposures of a similar dose and duration. These studies generally
use the same dose and duration at all ages, and thus do not have the type of issues discussed for
the repeated dosing studies. On the other hand, the acute dosing studies have limitations that
were sufficient to decide that they should not be included in the quantitative adjustment of cancer
potency. First, as mentioned in the previous paragraph, the large number of studies of lung
tumors with almost 100% response observed at all doses and all ages would significantly bias the
median ratio toward unity for a reason based on study design rather than biology. Second,
cancer potency estimates are usually derived from chronic exposures. Therefore, any adjustment
to those potencies should be, if possible, from similar exposures. Third, most exposures of
concern to the Agency are from repeated or chronic exposures rather than acute exposures.
Finally, many of the acute studies used ip exposures, which is not the usual route of exposure for
environmental chemicals. Thus, the repeated and lifetime studies are more appropriate for the
purpose of this analysis.
3.2.2. Carcinogens With Modes of Action Other Than Mutagenicity
Studies comparing tumors observed at the same sites following early postnatal and
chronic adult exposures in a single protocol were available for six chemicals that do not act
through a mutagenic mode of action [amitrole, dichlorodiphenyltrichloroethane (DDT), dieldrin,
ethylene thiourea (ETU), diphenylhydantoin (DPH), polybrominated biphenyls (PBB)] (Table 5).
19
-------
These chemicals cause tumors through several different, not necessarily well defined, modes of
action. For example, thyroid hormone disruption by ETU causes thyroid tumors; some PBBs act
through aryl hydrocarbon (Ah) receptors, while others are phenobarbital-like pleiotrophic
inducers of liver enzymes and liver tumors. Three of these studies evaluated only mouse liver
tumors (amitrole, DDT, dieldrin), while the other three evaluated a large number of tissues in
both mice and rats (ETU, DPH, PBB). These studies generally included a combined perinatal
and adult exposure as well as the separate perinatal or adult-only groups. It should be noted that
no acute perinatal dosing studies of carcinogenesis were identified for these agents; such
protocols are generally considered largely non-responsive for modes of action other than
mutagenicity and potent estrogenicity (e.g., DES).
For five chemicals (amitrole, DDT, dieldrin, PBB and DPH), the same tumors were
observed from early and/or adult exposures, though the studies for amitrole, DDT, and dieldrin
only evaluates the animals for liver tumors. With ETU, no tumors in mice or rats were observed
following perinatal exposure alone (except a small, not-statistically-significant increase in male
rat thyroid tumors), while thyroid tumors were observed in adult rats and thyroid, liver, and
pituitary tumors in adult mice. Analysis of the incidence of tumors per time of exposure shows
early-lifestage susceptibilities. The range of the magnitudes of the tumor incidence ratios of
juvenile to adult exposures is similar for the repeated dosing studies (0.06-13.3, weighted
geometric mean 2.2, 27% of ratios greater than 1, Tables 5 and 8) and lifetime dosing studies
(0.15-36, weighted geometric mean 3.4, 21% of ratios greater than 1, Tables 7 and 8). These
ranges and means are similar to those for chemicals with a mutagenic mode of action, though the
means and maximums are somewhat lower. Again, liver tumors are common to these chemicals.
The range of the magnitudes of liver tumor incidence ratios of juvenile to adult exposures also is
similar for the repeated dosing studies (0.06-13.3, weighted geometric mean 2.6, 43% of ratios
greater than 1, Tables 5 and 8) and lifetime dosing studies (0.15-36, weighted geometric mean
5.8, 33% of ratios greater than 1, Tables 7 and 8).
The major factor that complicates the interpretation of the results is that these studies,
except with DDT and dieldrin, involved dietary feeding initially to the mother, which potentially
could increase or decrease the dose received by the pups. Due to the maternal dosing during
pregnancy and lactation, the extent to which offspring received similar doses during different
early and adult lifestages is particularly uncertain for DPH, ETU, and PBBs. Oral gavage doses
in young animals were selected to approximate the average daily dose in adult dietary studies
based on standard estimates of feed consumption in the studies with DDT and dieldrin, while the
amitrole study involved dietary feeding postnatally to the mother so the young were dosed via
lactation. In addition, DDT, dieldrin, and some PBBs are more persistent in the body than are
20
-------
most chemicals, leading to a prolonged exposure even following limited dosing. Thus, these
studies provide evidence that early lifestages can be more susceptible to exposures to chemicals
causing cancer through a variety of modes of action other than mutagenicity. However, the
studies with ethylene thiourea, which acts via thyroid disruption, indicate that this is not
necessarily the case for all modes of action.
3.2.3. Ionizing Radiation
As mentioned previously, the UNSCEAR, Annex I (2000) includes information derived
from a wide range of both intentional (generally diagnostic or therapeutic medical) and
accidental radiation exposures. Only information derived from the Japanese population (referred
to as the Life Span Study in the UNSCEAR Annex I) is presented here. A statistically significant
excess cancer mortality associated with radiation has been found among the bomb survivors for
the following types of cancer: esophagus, stomach, colon, liver, lung, bone and connective
tissue, skin, breast, urinary tract, and leukemia. Tables 9 and 10 are extracted from the tables in
UNSCEAR, Annex I. The excess relative risk (ERR) is the increased cancer rate relative to an
unexposed population; an ERR of 1 corresponds to a doubling of the cancer rate. Because of the
low numbers of cancers in individual sites within narrow age groups, the ERRs for the various
solid tumors and leukemia were presented only as less than or greater than 20 years of age at the
time of exposure. The larger number of thyroid tumors enable a more detailed breakout shown in
Table 10. Most sites show greater risks in the younger than in the older ages.
The U.S. EPA (1994) document presents a methodology for estimation of cancer risks in
the U.S. population due to low-LET (linear energy transfer) radiation exposures using data from
the Atomic Bomb Survivor Study (ABSS) as well as from selected medical exposures. The
report developed mortality risk coefficients using several models that took into account age and
gender dependence of dosimetry, radiogenic risk, and competing causes of death as well as
transporting of risks across populations. The risk projections were updated using more recent
vital statistics in a report that also included an uncertainty analysis (U.S. EPA, 1999). Details of
the derivation of these coefficients are available at
http://www.epa.gov/radiation/docs/rad_risk.pdf.
Table 11 contains the calculated age-specific risk coefficients derived from the
application of the various models to the ABSS data. For most of the sites in the table, the risk
coefficients are higher in the earlier age groups; liver, bone, skin, and kidney coefficients are
age-independent and only esophageal cancer coefficients increase with increasing age. Also of
note is that the coefficients generally are higher for females. Similar to the information from the
UNSCEAR (2000) Annex, most sites show greater risks in the younger ages than the older ages.
21
-------
However, a comparison of the two tables seems to show reversal of risks for some sites as a
function of age at exposure. While the high sampling variability in the epidemiological data for
some ages may contribute to this apparent reversal, the choice of risk models and associated
parameters also is a factor.
22
-------
4. DISCUSSION
The challenge for this analysis was how to use the existing, but limited, scientific
database on early postnatal and juvenile exposures to carcinogens to inform a science policy
decision on whether, and if so how, to assess the risk from childhood exposures to chemicals for
which we have evidence of carcinogen!city only in adult humans or sexually mature laboratory
animals. The database overall is of limited size (particularly compared with the number of
chemicals that have been studied in adult occupational epidemiological studies or chronic
bioassays). The majority of the human data involves exposures to ionizing radiation or DES
(Anderson et al., 2000). More than 50 chemicals have been demonstrated to cause cancer
following perinatal exposures in animals (without adult exposures), but only a subset of the
chemicals have comparative studies across ages. The comparative experimental studies used 18
chemicals, 12 of which had mutagenic modes of action and 6 of which had data from repeated or
lifetime exposures. Other analyses of similar data have found similar results (Hattis et al. 2005),
but have focused on other aspects of the data, e.g., gender differences.
Previously published or internal U.S. EPA analyses have concluded that the standard
animal bioassay protocols usually do not miss chemicals that would have been identified as
carcinogens if perinatal exposures had been undertaken (McConnell, 1992; Miller et al., 2002;
U.S. EPA, 1996). Given the increased complexity and costs of chronic bioassays with perinatal
exposures, a limited number of such studies have been performed. However, these are the
studies that largely constitute the available database for this analysis. In addition to the chronic
bioassays with perinatal exposures, there are studies with acute dosing at different lifestages and
a large number of studies with perinatal exposures without a directly comparative adult study.
Two other kinds of information can contribute toward developing a scientifically
informed policy: theoretical analyses and analyses of stop studies.4 Theoretical analyses suggest
that the differential susceptibility would depend in part on the mode of action (i.e., at what step
in the cancer process(s) the chemical was acting) and that the use of the average daily exposure
prorated over a lifetime may underestimate or overestimate the cancer risk when exposures are
time-dependent (Goddard and Krewski, 1995; Murdoch et al., 1992). Evidence for old-
age-dependent promotion of basophilic foci in rats by peroxisome proliferators appears to
provide a concrete example consistent with these theoretical analyses (Cattley et al., 1991;
Kraupp-Grasl et al., 1991). The stop studies performed by the National Toxicology Program
began exposure at the standard post-weaning age, but stopped exposure after varying periods of
months. Other groups of animals were exposed for a full two years; all animals were evaluated
4 Stop studies are studies in which exposure is halted after a predetermined period.
23
-------
for tumors at the end of two years regardless of the duration of exposure (Halmes et al., 2000).
Related data also are available from the stop studies with vinyl chloride (Drew et al., 1983).
Analysis by Halmes et al. (2000) showed that, for six of the eleven chemicals and half the tumor
sites, the assumption that the cancer risk would be equal when the product of concentration and
time (i.e., C x T) was constant was incorrect, and usually underestimated risk, as more of the risk
came from the beginning of the exposure rather than the end. This dependence of risk on both
duration and intensity of exposure did not appear to be correlated with mutagenicity. It should
be noted that these stop studies all involved exposures early in the life of the animal (as opposed
to a limited number of cancer studies that looked at later periods of life; e.g., Drew et al., 1983),
but the extent to which the differences in tumor outcome result from increased susceptibility in
these early periods or the extended period for expression of the cancer cannot be evaluated.
These stop studies also used doses as high as or higher than the highest dose used in the two-year
exposure. This latter factor clearly had a significant effect for two chemicals, causing tumors at
higher doses that were not observed at lower doses. These results suggest that pharmacokinetic
or other dose-rate dependencies can make the effects of exposures at high doses different from
those exposures at lower doses. While not directly informative about early childhood exposures,
these studies provide a perspective on the common cancer risk assessment practice of averaging
exposures over a lifetime, especially those that include earlier lifestages. Thus, alternative
methods for estimating risks from short-term exposures during childhood should be considered.
Information on different lifestage susceptibilities to cancer risks for humans exists for
ionizing radiation. The effects of chemical mutagens at different lifestages on cancer induction
are derived from laboratory animal studies. While the induction of cancer by ionizing radiation
and the induction of cancer by chemical mutagens are not identical processes, both involve direct
damage to DNA as critical causal steps in the process. In both cases, the impacts of early
exposure can be greater than the impacts of later exposures, probably due to some combination
of early-lifestage susceptibility and the longer periods for observation of effects. As indicated in
Tables 9 and 10, A-bomb survivors exhibited different lifestage dependencies at different tumor
sites, though the total radiation-related incidence of tumors showed a general slow decline with
age at exposure. However, as previously noted, there are apparent differences at some sites
between the two tables. In addition to the sampling and modeling differences, the excess risk
values in Table 9 are based on Japanese baselines while the coefficients in Table 10 reflect
UNSCEAR's effort to transport the risks from the Japanese population to that of the United
States. However, it is clear that the total radiation-related tumor incidence showed a general slow
decline with age at exposure.
The studies in rodents of chemicals with mutagenic modes of action similarly support a
24
-------
general decline in induced cancer risk with age at exposure and similarly show some differences
for individual tumor sites. In general, the earliest two or three postnatal weeks in mice and rats
appeared to be the most susceptible, though some degree of increased susceptibility through
puberty in rats (beginning around 5-7 weeks) and mice (beginning around 4-6 weeks) for some
types of tumors exists.
All the acute dosing studies that demonstrated carcinogenicity with animals of different
ages used chemicals with a mutagenic mode of action (Tables 4 and 6). These studies provide
the clearest demonstrations of periods of differential susceptibility because the exposure rate is
constant at the different ages. The repeated dose studies also include several of the most
informative studies for assessing perinatal carcinogenesis, notably those on vinyl chloride and
DEN (Tables 2 and 4). The vinyl chloride studies by Maltoni and colleagues are part of a large
series of studies on this compound that included exposures to different concentrations for
varying durations, including some at early lifestages (Maltoni et al., 1984). The DEN study by
Peto et al. (1984) used a unique chronic study design in which groups of rats were exposed to
multiple drinking water concentrations starting at 3, 6, or 20 weeks of life. This design provides
information on the susceptibility of early exposure periods within a nearly lifetime exposure.
Beyond the analysis described here, there are conceptual biological rationales that would
suggest DNA-damaging agents would have greater impacts on early lifestages. Growth involves
substantial levels of cell replication, even in organs that in adults are only very slowly
replicating, thus increasing the likelihood that a cell will undergo division before the DNA
damage caused by the mutagen has been repaired. Increased replication also can lead to a
greater division of initiated cells, leading to a larger number of initiated cells per specified dose.
These periods of cell replication can vary for different tissues. For example, DMBA appears to
be more effective at initiating mammary tumors in 6-8 week old rats, which are undergoing
development of that tissue, than during earlier or later periods (Meranze et al., 1969). While
tumor promotion processes can be very dependent upon the duration of promotion, initiation
processes can occur in relatively brief periods (e.g., the single-dose studies in animals or
radiation exposure in humans). Most tumors take extended periods to develop, making damage
that occurs earlier in life more likely to result in tumors prior to death than would exposures that
occur later in life. While some of these observations may also pertain to other modes, all of them
(with some differences among tumor sites) appear to be potentially relevant to a greater
susceptibility to mutagenic modes of action during early-life stages (vs. later-life stages).
The information on lifestage susceptibility for chemicals inducing cancers through modes
of action other than direct DNA interaction is more varied, showing an increase in tumor
incidence during perinatal exposure versus exposures of mature animals (e.g., polybrominated
25
-------
biphenyls induced liver tumors), no tumors from perinatal exposure (e.g., ethylene thiourea
induced thyroid tumors), no effect of combined perinatal and adult exposure (e.g., DPH liver
tumors in rats and female mice), and different tumors from perinatal exposure versus adult
exposure (e.g., DBS, ascorbate). These variations are likely a result of the modes of action of
these chemicals and the pharmacokinetic differences in doses during different periods of life. No
studies were evaluated that were directly comparable to the single-dose studies with mutagens,
which clearly show significant differences in tumor responses after explicitly controlled doses at
different lifestages.
Some evidence for an effect of early-lifestage exposures on tumor incidence was
observed in studies with polybrominated biphenyls, amitrole, DDT, dieldrin, and
diphenylhydantoin. These studies show increased incidence of tumors in mice from perinatal
exposure, though only those for polybrominated biphenyls were statistically significant. (A
nonstatistically significant increase also was observed in male rats with polybrominated
biphenyls.) Combined perinatal and adult exposures generally gave statistically significant
increases, though not necessarily for each sex and species (rat and mice) in the
diphenylhydantoin and polybrominated biphenyl studies.
There are important demonstrations of chemicals acting through modes of action other
than mutagenic to cause different tumor types with early-lifestage exposures compared with
exposures for adults, e.g., tamoxifen and DES (Carthew et al., 2000; Carthew et al., 1996, Gass
et al., 1964; Newbold et al., 1990, 1997, 1998). In addition, studies with in utero exposure to
atrazine (Fenton and Davis, 2002), DES, and arsenic (Waalkes et al., 2003) indicate that early-
life exposures to compounds can alter susceptibility of endocrine and reproductive organs. Three
of these compounds (i.e., DES, genistein, and tamoxifen) bind to the estrogen receptor. Ongoing
studies on ethinyl estradiol, nonylphenol, and genistein by the National Toxicology Program will
add to this database for estrogens (Laurenzana et al., 2002; Newbold et al., 2001). These studies
will evaluate cancer incidence in offspring exposed in utero, during lactation, and through
adulthood via diet. A study with genistein found uterine tumor development to be dependent
upon early-lifestage exposures (Newbold et al., 2001). Another recent study of estrogen found a
shorter latency for mammary tumors in mice exposed at 8 and 12 weeks as compared to mice
exposed at 4 or 18 weeks, indicating a susceptible period between 8 to 12 weeks of exposure
(Yang, 2003). Thus, there is an actively growing database from which to consider issues of
childhood exposure and cancer for compounds acting through the estrogen receptor or other
mechanisms of endocrine disruption.
The ability to estimate with any accuracy the juvenile to adult cancer potency ratio
depends very much on the experimental design used. The lifetime design has less ability to
26
-------
distinguish increased susceptibility from early-life exposure than the other types of designs.
Consider two different experimental designs. In the first, the "lifetime" design, a group of
animals are exposed starting as juveniles, and exposure continues through adulthood. A second
group are exposed only in adulthood, and the juvenile:adult ratio results from a comparison of
tumor incidences in the two groups. In the second, the "repeated" design, one group of animals
is exposed only during the juvenile period, and is then followed through adulthood to assess
tumor incidence, and a second group of animals is exposed only through adulthood. The lifetime
design turns out to be a particularly insensitive design for estimating the juvenile:adult ratio.
The following example demonstrates the magnitude of the problem: Suppose the risk per
day of exposure of a chemical is ten fold greater in the juvenile period as in the adult period, and
animals exposed through adulthood at a particular dose level have an extra risk of 60% for
having at least one tumor, while 1% of control animals have tumors. The adult exposure period
is 94 weeks, while the juvenile exposure period is 4 weeks. Thus, in the lifetime design, the
group of animals exposed as juveniles will receive a total of 98 weeks of exposure, (4 in juvenile
and 94 in adult), while those receiving the adult-only exposure receive 94 weeks of exposure. In
the repeated design, animals exposed as juveniles receive only 4 weeks of exposure, while the
adults receive 94 weeks, just as in the lifetime design. Each group starts with 50 animals. Under
these assumptions, using equations (1) and (2) from Section 2.3, the expected number of animals
with tumors in the three treatment groups (control, juvenile-exposed, adult-exposed groups) in
the two designs is:
Number of animals with tumors
Control Early-life exposure Adult exposure
Lifetime 1 36 30
Repeated 1 16 30
Notice that in the "lifetime" design, only six more juvenile-exposed animals have tumors
than in the adult-exposed group, whereas in the "repeated" design, 16 juvenile-exposed animals
have tumors. The data in the lifetime design are consistent with the hypothesis of no tumors
being induced during the juvenile period: the ratios 36/50 and 30/50 are not statistically
significantly different. In other words, the data from the lifetime design are statistically
consistent with the hypothesis of no risk at all during the juvenile period, even though the real
response is a 10 times greater risk from early-life exposure. The difference between the results
from the two different study designs is due to the one-hit model: each additional week of a long
exposure contributes less than the previous week to the total number of animals with tumors.
27
-------
Note that, even if the one-hit model is not correct, chronic exposure probably results in a non-
statistically significant increase for the lifetime exposure including juveniles as compared with
only adult exposure.
The proper measure of relative potency of an exposure in the juvenile period relative to
an exposure in the adult period is the ratio of doses in the two periods that give the same
incidence of tumors. However, most of the data sets used in this report contained only one non-
control dose, precluding the extensive dose-response modeling that would be required to
estimate this ratio of doses. However, this document largely considered chemicals for which a
mutagenic mode of action has been established and for which a linear, no-threshold dose-
response function is assumed for the low-dose range being considered for risk assessment. In the
case of the linear dose-response function, the analysis of the relative response from the same
dose will produce the same value as ratio of doses that produces the same incidence of tumors.
For a one-hit dose-response equation, the probability of developing a tumor after the
same dose and duration in the juvenile or adult period is
for dose x. Suppose we want to calculate the dose Da or D} that results in a given incidence of
tumors after an adult or juvenile exposure. From equation 1, Da and D}- equal:
D =
Thus, the ratio DJDj = m/ma, the ratio calculated in this document.
In summary, this analysis supports the conclusion that there can be greater susceptibility
for the development of tumors as a result of exposures to chemicals acting through a mutagenic
mode of action, when the exposures occur in early lifestages as compared with later lifestages.
Thus, this Supplemental Guidance recommends for chemicals with a mutagenic mode of action
for carcinogenesis when chemical-specific data on early-life exposure are absent, a default
28
-------
approach using estimates from chronic studies (i.e., cancer slope factors) with appropriate
modifications to address the potential for differential risk of early-lifestage exposure. For
chemicals acting through a non-mutagenic mode of action, e.g., hormonally mediated
carcinogens, the available data suggest that other approaches may need to be developed for
addressing cancer risk estimates from childhood exposures. This is a particular concern because
the tumors arising from hormonally active chemicals appear to involve different sites when
exposure is during early-life versus adulthood, an effect that has been observed relatively
infrequently. Development of such approaches would require additional research to provide an
expanded scientific basis for their support, including additional research and the possible
development of new toxicity testing protocols that consider early lifestage dosing.
The current data do also not allow analysis of some issues of potential interest for risk
assessment, e.g., potential increased risk of childhood cancer, from in utero or childhood
exposures. Assessing the role of environmental exposures on childhood cancers is difficult, but
additional research could include epidemiological studies or experimental studies with animals
genetically designed to express cancers analogous to human childhood cancers. Rigorous
quantification of exposure doses at different lifestages and in rodent pups in experimental studies
would be useful for evaluating whether there is greater childhood susceptibility.
Pharmacokinetic modeling could better define the internal doses to improve determination of the
magnitude of increased susceptibility.
29
-------
5. GUIDANCE FOR ASSESSING CANCER RISKS
FROM EARLY-LIFE EXPOSURE
Consistent with the approach and recommendations of the U.S. EPA cancer risk
assessment guidelines (U.S. EPA, 2004), any assessment of cancer susceptibility will begin with
a critical analysis of the available information. Figure 3 shows the proposed steps in the process.
The potential for increased susceptibility to cancer from early-life exposure, relative to
comparable exposure later in life, generally warrants explicit consideration for each assessment.
When developing quantitative estimates of cancer risk, the Agency recommends
integration of age-specific values for both exposure and toxi city/potency where such data are
available and appropriate. Children, in general, are expected to have some exposures that differ
from those of adults (either higher or lower), due to differences in size, physiology, and
behavior. For example, children are generally assumed to eat more food and drink more water
relative to their body weight than adults. Children's normal activities, such as putting their hands
into their mouths or playing on the ground, can result in exposures to contaminants that adults do
not encounter. Moreover, children and adults exposed to the same concentration of an agent in
food, water, or air may receive different (higher or lower) internal doses due to differences, for
example, in intake, metabolism, or absorption rates. Children are less likely than adults to be
exposed to products typically used in industrial settings and often have more limited diets than
adults. When assessing risks, if the data are available and relevant, it is important to include
exposure that is measured or modeled for all lifestages, including exposures during childhood
and during adulthood. EPA continues to develop better tools for assessing childhood exposure
differences, such as the Child-Specific Exposure Factors Handbook (U.S. EPA, 2002a), and
models, such as Stochastic Human Exposure and Dose Simulation (SHEDS) and Consolidated
Human Activity Database (CHAD) (McCurdy et al., 2000; Zartarian et al., 2000)
Mode-of-action studies can be a source of data on quantitative differences between
children and adults (Figure 3, Box 1). If the available information is sufficient to establish the
agent's mode of action for early-life and adult exposures, then the implications for early-life
exposure of that mode of action are used to develop separate risk estimates for childhood
exposure. Pertinent information can be obtained both from agent-specific studies and from other
30
-------
studies that investigate the general properties of the particular mode of action. All data
indicating quantitative differences between children and adults are considered in developing
those portion(s) of the risk estimates for exposure estimates that include childhood exposure.
Some examples include the potential for children to have a different internal dose of the active
agent or a change in a key precursor event (see Section 2.43.4 of the Guidelines for Cancer Risk
Assessment}.
When the mode of action cannot be established (Figure 3, Box 2), the policy choice
would be to use linear extrapolation to lower doses such that risk estimates are based on a
lifetime average daily exposure without further adjustment. No general adjustment is
recommended at this time. This policy choice is consistent with past U.S. EPA practice that has
been favorably evaluated over the years. The result would be expected to produce plausible
upper bound risk estimates, based on the use of linear extrapolation as a default in the absence of
information on the likely shape of the dose-response curve.
When a mode of action other than mutagenicity is established, if it is nonlinear (Figure 3,
Box 3) or linear (Figure 3, Box 4), no general adjustment is recommended at this time. Although
the available studies (discussed previously) indicates that higher or lower cancer risks may result
from early-life exposure, there is insufficient information or analyses currently available to
determine a general adjustment at this time. As other modes of action become better understood,
this information may include data on quantitative differences between children and adults. If
such data are available, an analysis of the differences could be used to adjust risk estimates for
childhood exposure. EPA expects to expand this Supplemental Guidance to specifically address
modes of action other than mutagenicity when sufficient data are available and analyzed.
When the data indicate a mutagenic mode of action,5 the available studies (discussed
5 Determination of chemicals that are operating by a mutagenic mode of action entails evaluation of test results for
genetic endpoints, metabolic profiles, physicochemical properties, and structure-activity analyses in a weight-of-
evidence approach (Waters et al., 1999). Established protocols are used to generate the data (Cimino, 2001; OECD,
1998; U.S. EPA, 2002b); however, it is recognized that newer methods and technologies such as those arising from
genomics can provide useful data and insights to a mutagenic mode of action. Carcinogens acting through a
mutagenic mode of action generally interact with DNA and can produce such effects as DNA adducts and/or
breakage. Carcinogens with a mutagenic mode of action often produce positive effects in multiple test systems for
different genetic endpoints, particularly gene mutations and structural chromosome aberrations, and in tests
performed in vivo, which generally are supported by those performed in vitro. This mode of action is addressed in
more detail in Section 2.3.5 of EPA's cancer guidelines (U.S. EPA, 2005).
-------
above) indicate higher cancer risks resulting from a given exposure occurring early in life when
compared with the same amount of exposure during adulthood. However, chemical-specific data
relating to mode of action (e.g., toxicokinetic or toxicodynamic information) may suggest that
even though a compound has a mutagenic mode of action, higher cancer risks may not result.
Such data should be considered before applying the age-dependent adjustment factors.
If the available, chemical-specific information includes an epidemiologic study of the
effects of childhood exposure or an animal bioassay involving early-life exposure (Figure 3, Box
5), then these studies are analyzed to develop risk estimates (i.e., cancer slope factors) that
specifically address any potential for differential potency in early lifestages. An example is the
IRIS assessment of vinyl chloride (U.S. EPA, 2000b; c).
In the absence of early-life studies on a specific chemical under consideration (Figure 3,
Box 6), the extrapolation from the point of departure to lower doses employs linear extrapolation
(see Section 3.3.1 of the U.S. EPA [2005] cancer guidelines). This choice is based on mode-of-
action data indicating that mutagens can give rise to cancers with an apparently low-dose linear
response. Adjustments to the resultant risk estimates are specified with regard to childhood
exposures. This approach is adopted because risk estimates based on an average daily exposure
prorated over a lifetime do not consider the potential for higher cancer risks from early-life
exposure.
The adjustments described below reflect the potential for early-life exposure to make a
greater contribution to cancers appearing later in life. The 10-fold adjustment represents an
approximation of the weighted geometric mean tumor incidence ratio from juvenile or adult
exposures in the repeated dosing studies (see Table 8). This adjustment is applied for the first 2
years of life, when toxicokinetic and toxicodynamic differences between children and adults are
greatest (Ginsberg et al., 2002; Renwick, 1998). Toxicokinetic differences from adults, which
are greatest at birth, resolve by approximately 6 months to 1 year, while higher growth rates
extend for longer periods. The 3-fold adjustment represents an intermediate level of adjustment
that is applied after 2 years of age through <16 years of age. This upper age limit represents
middle adolescence following the period of rapid developmental changes in puberty and the
conclusion of growth in body height in NHANES data (Hattis et al., 2005). Efforts to map the
approximate start of mouse and rat bioassays (i.e., 60 days) to equivalent ages in humans ranged
from 10.6 to 15.1 years (Hattis et al., 2005). Data are not available to calculate a specific dose-
response adjustment factor for the 2 to <16-year age range, so EPA selected the 3-fold
32
-------
adjustment because it reflects a midpoint, i.e., approximately half the difference between 1 and
10 on a logarithmic scale (101/2), between the 10-fold adjustment for the first two years of life
and no adjustment (i.e., 1-fold) for adult exposure. EPA also recognizes that exposures
occurring near the end of life may have little effect on lifetime cancer risk, but lacks adequate
data at present to provide an adjustment for this "wasted dose" effect. Similarly, since most of
the studies involved only one latency period, the potential effect of early-life exposure on latency
for the observed tumors could not be evaluated. The lack of data on effect on latency also
limited the types of analyses that could be performed, e.g., more complex dose-response
functions, such as multi-stage or clonal expansion models, could not be evaluated. Thus, the
potential effects of early-life exposures on latency were not evaluated. Finally, as the adjustment
factors are derived from a weighted geometric mean of the data evaluated, these adjustment will
both over-estimate and under-estimate the potential potency for early-life exposure for chemicals
with a mutagenic mode of action for carcinogenesis. An examination of the data in the tables
demonstrates that some of the ratios were less than one, while others exceeded 10. For this
reason, the Supplemental Guidance emphasizes that chemical-specific data should be used in
preference to these default adjustment factors whenever such data are available.
The following adjustments represent a practical approach that reflects the results of the
preceding analysis, which concluded that cancer risks generally are higher from early-life
exposure than from similar exposure durations later in life:
• For exposures before 2 years of age (i.e., spanning a 2-year time interval from the first
day of birth up until a child's second birthday), a 10-fold adjustment.
• For exposures between 2 and <16 years of age (i.e., spanning a 14-year time interval from
a child's second birthday up until their sixteenth birthday), a 3-fold adjustment.
• For exposures after turning 16 years of age, no adjustment.
Clearly other age groups, such as an age group experiencing pubertal changes in
physiology, or approximately ages 9-15, may experience changes in biological processes that
could lead to modifications in the susceptibility to the effects of some carcinogens, depending on
the mode of action. This Supplemental Guidance focuses on carcinogens with a mutagenic mode
33
-------
of action. For any mode of action, the Agency is interested in identifying lifestages that may be
particularly sensitive or refractory for carcinogenesis, and believes that the mode of action
framework as described by EPA's cancer guidelines (U.S. EPA, 2005), is an appropriate
mechanism for elucidating these lifestages. In general, the Agency's analyses of lifestages that
may be susceptible will depend on three factors: (1) establishing the mode of action for
carcinogenesis; (2) using knowledge about the biological and toxicological key events in that
mode of action that are likely to be affected by lifestages; and (3) the availability, or
development, of data that allow analysis of the effects of chemicals acting by that mode of action
during the relevant ages. For each mode of action evaluated, therefore, the various age groupings
determined to be at a differential risk, which may differ significantly from those proposed for the
mutagenic mode of action, are expected to be evaluated independently of other modes of action.
When data, including well established mode of action data, are available that allow specific
evaluation of lifestage differences in toxicokinetics or toxicodynamics that would lead to lesser
or greater susceptibility from early-life exposures to carcinogens, then those data should be used,
as generally discussed in EPA's cancer guidelines (U.S. EPA, 2005), in preference to the default
procedures described in this Supplemental Guidance.
The 10-fold and 3-fold adjustments in slope factor are to be combined with age-specific
exposure estimates when estimating cancer risks from early life exposure to carcinogens that act
through a mutagenic mode of action. It is important to emphasize that these adjustments are
combined with corresponding age-specific estimates of exposure to assess cancer risk. For
example, for a 70-year lifetime, where there are data showing negligible exposure to children,
the estimated cancer risk from childhood exposure would be also negligible and the lifetime
cancer risk would be reduced to that resulting from the relevant number of years of adult
exposure (in the absence of specific information, 55 years). Where there are data (measured or
modeled) for childhood exposures, the age-group specific exposure values are used along with
the corresponding adjustments to the slope factor. Where there are no relevant data or models
for childhood exposures and only lifetime average exposure data are available, the lifetime
exposure data are used with the adjustments to the slope factor for each age segment.
It is recognized that, when the exposure is fairly uniform over a lifetime, the effect of
these adjustments on estimated lifetime cancer risk are small relative to the overall uncertainty of
34
-------
such estimates. These adjustments can be applied when estimating the cancer risk resulting from
childhood exposure. These adjustments are applied when developing risk estimates from
conventional animal bioassays or epidemiologic studies of effects of adult exposure. Some
examples follow in the next section.
The Agency has also carefully considered both the advantages and disadvantages to
extending the default potency adjustment factors to carcinogenic chemicals for which the mode
of action remains unknown. It is the Agency's long-standing science policy position that use of
the linear low-dose extrapolation approach (without further adjustment) provides adequate public
health conservatism in the absence of chemical-specific data indicating differential early-life
susceptibility. At the present time, therefore, EPA is recommending these age-dependent
adjustment factors only for carcinogens acting through a mutagenic mode of action based on a
combination of analysis of available data and the above-mentioned science policy position. In
general, the Agency prefers to rely on analyses of data, rather than general defaults. When data
are available for a susceptible lifestage, they should be used directly to evaluate risks for that
chemical and that lifestage on a case-by-case basis. In this analysis, the data for non-mutagenic
carcinogens, when the mode of action is unknown, were judged to be too limited and the modes
of action too diverse to use this as a category for which a general default adjustment factor
approach can be applied.
35
-------
6 COMBINING LIFESTAGE DIFFERENCES IN EXPOSURE AND DOSE-
RESPONSE WHEN ASSESSING CARCINOGEN RISK - SOME EXAMPLES FOR
CARCINOGENS THAT ACT THROUGH A MUTAGENIC MODE OF ACTION
It is important for the risk assessor to consider lifestage differences in both exposure and
dose-response when assessing cancer risk resulting from early-life exposures. As discussed in
Section 5, age dependent adjustments factors (ADAFs) in dose response (i.e., slope factors) are
combined with age specific exposure estimates when assessing cancer risks. This is a departure
from the way cancer risks have historically been based upon the premise that risk is proportional
to the daily average of lifetime dose. This Supplemental Guidance recommends an integrative
approach that can be used to assess total lifetime risk resulting from lifetime or less-than-lifetime
exposure during a specific portion of a lifetime.
The following examples can help demonstrate how to apply this guidance by integrating
potential lifestage differences in exposure and/or dose-response (potency), and also demonstrate
what the resulting impacts are on calculated risks. These hypothetical examples consider risks
from both lifetime, as well as less-than-lifetime oral exposures. Risks associated with inhalation
exposure to carcinogens that act via a mutagenic mode of action are calculated in similar fashion
by applying the appropriate ADAF(s) along with the corresponding inhalation unit risk estimate,
using pertinent estimates of exposure concentration.
Note again, ADAFs are only to be used for agents with a mutagenic mode of action for
carcinogenesis when chemical-specific data are absent. For all modes of action, when chemical-
specific data are available for early-life exposure, those data should be used.
6.1 CALCULATING LIFETIME RISKS ASSOCIATED WITH LIFETIME EXPOSURES
Example 1: Consider a scenario of exposure to a carcinogen with a nonmutagenic mode of
action. Suppose the oral cancer slope factor derived from a typical animal study (i.e., where
dosing begins after puberty) is estimated to be 2 per mg/kg-d, and the exposure rate remains
constant throughout life at 0.0001 mg/kg-d (this is equivalent to saying the daily average of
lifetime dose rate is equal to 0.0001 mg/kg-d). The risk from lifetime exposure is calculated by
multiplying the slope factor and the exposure rate:
Risk = (2 per mg/kg-d) x (0.0001 mg/kg-d)
36
-------
2xlO'4
Example 2: Now consider the same exposure scenario for a carcinogen with a mutagenic mode
of action for which the oral cancer slope factor, derived from a typical animal study where
dosing begins after puberty, is also estimated to be 2 per mg/kg-d. In this case, ADAFs are used,
as follows.
a. To calculate lifetime risk for a population with average life expectancy of 70 years,
sum the risk associated with each of the three relevant time periods:
• Risk during the first 2 years of life (where the ADAF = 10);
• Risk for ages 2 through < 16 (ADAF = 3); and
• Risk for ages 16 until 70 years (ADAF = 1).
Thus, risk equals the sum of:
• Risk for birth through < 2 yr = (2 per mg/kg-d) x 10 (ADAF) x (0.0001 mg/kg-d)
x 2yr/70yr
= 0.6xlO'4
• Risk for ages 2 through < 16 = (2 per mg/kg-d) x 3 (ADAF) x (0.0001 mg/kg-d)
x(13yr/70yr)
= l.lxlO'4
• Risk for ages 16 until 70 = (2 per mg/kg-d) x 1 (ADAF) x (0.0001 mg/kg-d)
x (55yr/70yr)
= 1.6xlO'4
Risk =0.6xlO'4+l.lx 10'4+ 1.6 xlO'4
= 3.3xlO'4
b. If exposure varies with age, then such differences are also included. Now suppose the
same example as immediately above, except that exposure for ages 1 through <12 was
twice as high as exposure for all other ages. In this case, sum the risk associated with
each of the five relevant time periods in which exposure rates and/or potencies (slope
37
-------
factors) vary:
Risk equals the sum of:
• Risk for birth through < 1 yr (lyr) = (2 per mg/kg-d) x 10 (ADAF) x 0.0001 mg/kg-d
x lyr/70yr
= 0.3 x 10'4
• Risk for ages 1 through < 2 (lyr) = (2 per mg/kg-d) x 10 (ADAF) x 0.0002 mg/kg-d
x lyr/70 yr
= 0.6xlO'4
• Risk for ages 2 through < 12 (lOyr) = (2 per mg/kg-d) x 3 (ADAF) x 0.0002 mg/kg-d
x 10yr/70yr
= 1.7xlO'4
• Risk for ages 12 through < 16 (4yr) = (2 per mg/kg-d) x 3 (ADAF) x 0.0001 mg/kg-d
x 4yr/70yr
= 0.3 x 10'4
• Risk for ages 16 until 70 years (55yr) = (2 per mg/kg-d) x 1 (ADAF) x 0.0001 mg/kg-d
x 55yr/70yr
= 1.6xlO'4
Risk = 0.3 x 10'4 + 0.6 x 10'4 + 1.7 x 10'4 + 0.3 x 10'4 + 1.6 x 10'4
= 4.5x 10'4
6.2 CALCULATING LIFETIME RISKS ASSOCIATED WITH LESS THAN LIFETIME
EXPOSURES
If exposure only occurs for a limited number of years (for example, consider a family that
lives near a source of exposure for a five-year period of time before moving away), it is critical
to combine lifestage differences in exposure and dose-response for the relevant time interval.
The examples presented below demonstrate how adjusting potency and/or exposure can affect
the assessment of cancer risk.
38
-------
Example 3: If exposure to a carcinogen with a mutagenic mode of action with an oral slope
factor equal to 2 per mg/kg-d occurs during adulthood for only 5 years, the daily average of
lifetime dose is time weighted to apportion risk for the number of years of exposure by a factor
of 5/70:
Risk = (2 per mg/kg-d) x (0.0001 mg/kg-d) x (5yr/70yr)
= 1.4xlO'5
Example 4: If this 5-year exposure occurs during childhood, the risk calculations are adjusted to
consider the potential for higher potency from early-life exposure. Assessors should remember
that the age dependent adjustment factors for carcinogens with a mutagenic mode of action are
applied only to exposure periods occurring up to age 16.
a. For a child exposed between ages 5 and 10, only a 3-fold ADAF is applied because
the exposure occurs entirely between ages 2 and <16 years:
Risk =3 (ADAF) x (2 per mg/kg-d) x (0.0001 mg/kg-d) x (5 yr/70 yr)
= 4.3xlO'5
b. For an exposure between ages 13 and <18, a 3-fold ADAF is applied only to the
3-year portion occurring before age 16:
Risk equals the sum of:
• Risk for ages 13 through < 16 (Syr) = 3 (ADAF) x (2 per mg/kg-d) x (0.0001 mg/kg-d)
x (3 yr/70 yr)
= 2.6xlO'5
• Risk for ages 16 through < 18 (2yr) = 1 (ADAF) x (2 per mg/kg-d) x (0.0001 mg/kg-d)
x (2 yr/70 yr)
= 0.6xlO'5
Risk =2.6x10°+ 0.6x10'
-5
39
-------
= 3.2x10
-5
c. For a child exposed from birth through age 5, different ADAFs are applied to the
periods before and after age 2:
Risk equals the sum of:
• Risk for birth through < 2 (2yr)
• Risk for ages 2 through < 5 (3yr)
Risk =5.7xlO'5 + 2.6x 10'5
= 8.3x10
-5
= 10 (ADAF) x (2 per mg/kg-d) x (0.0001 mg/kg-d)
x (2 yr/70 yr)
= 5.7xlO'5
= 3 (ADAF) x (2 per mg/kg-d) x (0.0001 mg/kg-d)
x (3 yr/70 yr)
= 2.6x10
-5
Example 5: Lifetime risk calculations based on less-than-lifetime exposure to a carcinogen with
a mutagenic mode of action include any lifestage changes in potency as well as exposure. In this
example, again consider a scenario of 5 years of exposure to a carcinogen with a mutagenic
mode of action, but suppose that the exposure rate is found to vary from 0.0002 mg/kg-d during
the first 2 years of life, to 0.0001 mg/kg-d during the last 3 years.
a. For a child exposed between birth and age 5, sum the risk associated with the two
relevant time periods:
Risk equals the sum of:
40
-------
Risk for birth through < 2 (2yr)
• Risk for ages 2 through < 5 (3yr)
= 10 (ADAF) x (2 per mg/kg-d) x (0.0002 mg/kg-d)
x (2 yr/70 yr)
= 11.4xlO'5
= 3 (ADAF) x (2 per mg/kg-d) x (0.0001 mg/kg-d)
x (3 yr/70 yr)
= 2.6x10
-5
Risk = 11.4 x!0'5 +2.6 x 10'5
= 1.4xlO'4
b. For comparison, a similar risk calculation for 5 years of exposure later in life (after
age 16) in which the first 2 years of exposure are double that of the next 3 years are
carried out without any adjustment for potency:
Risk equals the sum of:
• Risk for first 2 years of adult exposure
Risk for final 3 years of adult exposure
Risk = l.lxlO'5 + 0.9x 10'5
= 2x 10"
= 1 (ADAF) x (2 per mg/kg-d)
x (0.0002 mg/kg-d) x (2yr/70yr)
= l.lxlO'5
= 1 (ADAF) x (2 per mg/kg-d)
x (0.0001 mg/kg-d) x (3yr/70yr)
= 0.9x10
-5
41
-------
Standard Rodent Cancer Study: Adult Exposure
Postnatal Exposure
Postnatal & Adult Exposure (Lifetime)
In utero, postnatal, & Adult Exposure (Lifetime)
In utero & postnatal Exposure
r i i
f t i
birth puberty Assessment
mating weaning of tumors
Figure 1. Study designs.
42
-------
1.0 H
o
a! 0.6 -
0)
3* 0.4 -
zt
E
O 0.2 -
0.0 -
10
-3
10
-2
I I
0.1 1 10
JuvenileiAdult Ratio
1.0 H
o.o -
10
-3
10
-2
0.1 1
JuvenileiAdult Ratio
Figure 2: Posterior, unweighted geometric means and 95% confidence intervals for the ratios of juvenile to
adult cancer potency for carcinogens acting primarily through a mutagenic mode of action. The top panel is
for repeated and lifetime exposure studies (geometric mean in black), the bottom panel is for acute exposure studies
mutagens (geometric mean in white). The horizontal lines to the left and right of each geometric mean correspond to
95% confidence limits. The vertical dark line represents the inverse-variance weighted geometric mean of the
posterior geometric means. The horizontal dark line represents the 95th percentile of the unweighted distribution,
with the vertical, dotted line establishing it value.
-------
Figure 3. Flow chart for early-life risk assessment using mode of action framework
Box 1: Use framework in Cancer Guidelines
to establish MOA(s)
MOA sufficiently
supported in animals?
MOA can not
be determined
Yes
MOA relevant to
humans?
No
Yes
Flag lifestage(s) or population(s) that
could be susceptible (based on
information about the specific MOA)
for dose-response analysis.
Nonlinear
Determine extrapolation
based on information
about specific MOA.
Linear, but
jionmutagenic
MOA
Linearity due to
mutagenic MOA
Box 2: Use linear
extrapolation as a default.
No further analysis of
tumors.
Box 3: Model using MOA or
use RfD/RfC method as default.
Adjustments for susceptible
lifestages or populations are part
of the process.
Box 4: Use the same linear
extrapolation for all lifestages,
unless have chemical-specific
information on lifestages or
populations.
Supplemental Guidance for Early-Life Exposures
Were chemical-specific data available
in MOA analysis to evaluate differences
between adults and juveniles (more,
less, or the same susceptibility)?
Yes
Box 5: Develop chemical-
specific risk estimates
incorporating lifestage
susceptibility.
No
Box 6: Early-life susceptibility assumed. Apply
age-dependent adjustment factors (ADAFs) as
appropriate to develop risk estimates.
-------
Table la. Chemicals that have been found to have carcinogenic effects from prenatal or postnatal exposure in
animals as identified in different review articles
Chemical name
4-Acetylaminobiphenyl (AAB)
4-Aminoazobenzene (AB)
3-Amino-l,4,-dimethyl-5H-pyrido[4,3-b]indole(Trp-P-l)
2-Aminodipyridol[l,2-a:3',2'-d]imidazole(Glu-P-2)
2-Amino-6-methyldipyridol[l,2-a:3',2'-d]imidazole(Glu-P-l)
3 - Amino- 1 -methyl-5H-pyrido [4, 3 -b] indole (Trp-P-2)
Amitrole
Arsenic
5-Azacytidine
3'-Azido-3'-deoxythymidine (AZT)
Azoxymethane
Benz [a] anthracene
Benzidine
Benzo[a]pyrene (BaP)
1 -(4'Bromophenylazo)- 1 -phenyl- 1 -hydroperoxymethane (BPH)
N-Butyl-N-(3-carboxypropyl)nitrosamine (BCPN)
N-Butyl-N-(3 hydroxbutyl)nitrosamine (BBN)
Butylnitrosourea (BNU)
Cyclophosphamide
Dibenz [a, h] anthracene (DBA)
Dibutylnitrosamine (DBN)
Dichlorodiphenyltrichloroethane (DDT)
Dieldrin
2-Diethylaminoethyl-2,2-dephenylvalerate hydrochloride
(SKF 525 A)
Review articles including prenatal and postnatal exposure
Fujii
(1991)
X
X
X
X
X
X
X
X
X
X
X
X
X
McClain
etal.
(2001)
X
Anderson
etal.
(2000)
X
X
X
X
Delia Porta
and
Terracini
(1969)
X
X
X
Other
literature
X
Chemicals
selected for
quantitative
analysis
X
X
X
X
X
X
-------
Table la. Chemicals that have been found to have carcinogenic effects from prenatal or postnatal exposure in
animals as identified in different review articles (continued)
Chemical name
Diethylnitrosamine (DEN)
Diethylstilbesterol (DBS)
4-Dimethylaminoazobenzene
1,2-Dimethylhydrazine (DMH)
7, 12-Dimethylbenz[a]anthracene (DMBA)
Dimethylnitrosamine (DMN)
5',5'-Diphenylhydantoin (DPH)
Estradiol
6-Ethoxy-2,2,4-trimethyl- 1 ,2-dihydroquinoline (Santoquin)
Ethylene thiourea (ETU)
Ethyl methane sulphonate
Ethylnitrosobiuret
Ethylnitrosourea (ENU)
N-2-Fluorenylacetamide (FAA)
Genistein
3 -Hydroxyl-4-acetylaminobiphenyl (N-OH-AAB)
N-2-Hydroxy-N-2-fluorenylacetamide(N-OH-FAA)
2-Hydroxypropyl-propylnitrosamine
9-Methylanthracene
Methyl-2-benzylhydrazine
Methylcholanthrene
3 -Methyl-4-dimethylaminoabenzene (3 'ME -DAB)
4-(Methylnitrosoamino)- 1 -(3 -pyridyl)- 1 -butanone (NNK)
Methylnitrosourea (NMU)
Methylnitrosourethane
1 -Methyl-3 -nitro- 1 -nitrosoguanidine (MNNG)
Review articles including prenatal and postnatal exposure
Fujii
(1991)
X
X
X
X
X
X
X
X
X
X
X
McClain
etal.
(2001)
X
Anderson
etal.
(2000)
X
X
X
X
X
X
X
X
X
X
X
X
Delia Porta
and
Terracini
(1969)
X
X
X
X
X
X
X
Other
literature
X
Chemicals
selected for
quantitative
analysis
X
X
X
X
X
X
>
-------
Table la. Chemicals that have been found to have carcinogenic effects from prenatal or postnatal exposure in
animals as identified in different review articles (continued)
Chemical name
2-Naphthylamine
2-Naphthylhydroxyamine
Nickel acetate
N-Nitrosobuylamine
4-Nitroquinoline- 1 -oxide
N-Nitrosomethyl(2-oxopropyl)amine
2-Oxopropyl-propylnitrosamine
1 -Pheny 1-3 , 3 ',-dimethy Ihy drzine
1 -Phenyl-3 ,3 ,-dimethy Itriazene
Polybrominated biphenyls (PBBs)
Safrole (3,4-methylenedioxyally benzene)
Soot
Sterigmatocystin
Tamoxifen
l,3,5-Trimethyl-2,4,6-tris[3,5-di-tert-butyl-4-
hydroxybenzyljbenzene (lonox 33)
Urethane (ethyl carbamate)
Vinyl chloride
Review articles including prenatal and postnatal exposure
Fujii
(1991)
X
X
X
X
McClain
etal.
(2001)
Anderson
etal.
(2000)
X
X
X
X
X
X
X
X
X
Delia Porta
and
Terracini
(1969)
X
X
X
X
Other
literature
X
Chemicals
selected for
quantitative
analysis
X
X
X
X
>
-------
Table Ib. List of chemicals considered in this analysis. (These are chemicals
for which both early-life and adult exposure are reported in the same animal
experiment.)
Chemical
Amitrole
Benzidine
Benzo[a]pyrene (BaP)
Dibenzanthracene (DBA)
Dichlorodiphenyltrichloroethane
(DDT)
Dieldrin
Diethylnitrosamine (DEN)
Dimethylbenz[a]anthracene
(DMBA)
Dimethylnitrosamine (DMN)
Diphenylhydantoin, 5,5- (DPH)
Ethylnitrosourea (ENU)
Ethylene thiourea (ETU)
3-Methylcholanthrene (3-MU)a
Methylnitrosourea (NMU)
Polybrominated biphenyls
(PBBs)
Safrole
Urethane
Vinyl chloride (VC)
References
Vesselinovitch(1983)
Vesselinovitch et al. (1975b)
Vesselinovitch et al. (1975a)
Law (1940)
Vesselinovitch et al. (1979)
Vesselinovitch et al. (1979)
Petoetal. (1984)
Vesselinovitch et al. (1984)
Meranze et al. (1969)
Pietraetal. (1961)
Walters (1966)
Hard (1979)
Chhabraetal. (1993b)
Naitoetal. (1981)
Vesselinovitch et al. (1974)
Vesselinovitch (1983)
Chhabraetal. (1992)
Klein (1959)
Terracini and Testa (1970)
Terracini et al. (1976)
Chhabraetal. (1993a)
Vesselinovitch et al. (1979)
Chieco-Bianchi et al. (1963)
Choudari Kommineni et al. (1970)
De Benedictis et al. (1962)
Fiore-Donati et al. (1962)
Klein (1966)
Liebeltetal. (1964)
Rogers (1951)
Maltoni et al. (1984)
Study type
Repeat dosing
Repeat dosing
Acute exposure
Acute exposure
Repeat dosing
Lifetime exposure
Repeat dosing
Lifetime exposure
Lifetime exposure
Acute exposure
Acute exposure
Acute exposure
Acute exposure
Acute exposure
Repeat dosing
Lifetime exposure
Acute exposure
Acute exposure
Acute exposure
Repeat dosing
Lifetime exposure
Repeat dosing
Acute exposure
Acute exposure
Repeat dosing
Lifetime exposure
Repeat dosing
Lifetime exposure
Acute exposure
Acute exposure
Acute exposure
Acute exposure
Acute exposure
Lifetime exposure
Acute exposure
Acute exposure
Repeat dosing
Mutagenic
mode of action
X
X
X
X
X
X
X
X
X
X
X
X
' Formerly known as 20-methylcholanthrene.
A-4
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures
Chemical
Amitrole
Benzidine
DDT
Dichlorodiphenyl-
trichloroethane
Species
(strain)
Mice
(B6C3FO
Mice
(B6C3FO
Mice
(B6C3FO
Target
site
liver
liver
liver
Age when
first dosed
Control
Gestation
day 12
Newborn
At weaning
Control
Gestation
day 12
Newborn
At weaning
Gestation
day 12
Gestation
day 12
Control
Weekl
WeekS
Weekl
Dose
route,
# doses
None
Diet, to
mothers
Diet, to
mothers
Diet, to
offspring
None
Diet, to
mothers
Diet, to
mothers
Diet, to
offspring
Diet, to
mothers
Diet, to
mothers
None
Gavage,
daily
Diet,
daily
Gavage,
daily until
4 weeks,
then in
diet
Dose
Control:
0 ppm
500 ppm
500 ppm
500 ppm
Control:
0 ppm
150 ppm
150 ppm
150 ppm
150 ppm
150 ppm
Control:
0 ppm
230 ug
150 ppm
230 ug
150 ppm
(diet)
Duration of
exposure
N/A
Gestation day
12 to delivery
Birth until
weaning
From weaning
to 90 weeks
N/A
Gestation day
12 to delivery
Birth until
weaning
From weaning
to 90 weeks
Gestation day
12 until
weaning
Gestation day
12 until 90
weeks
N/A
Weeks 1-4
Weeks 5-90
Weeks 1-90
Age at
death
90 weeks
90 weeks
90 weeks
Tumors"
M
1/98
(1%)
6/74
(8%)"
10/45
(22%)b
20/55
(36%)b
1/98
(1%)
17/55
(31%)c
62/65
(95%)c
22/50
(44%)c
49/49
(100%)c
50/50
(100%)c
1/50
(2%)
5/49
(10%)d
8/49
(16%)d
10/50
(20%)c
F
0/96
(0%)
0/83
(0%)b
0/55
(0%)b
9/49
(18%)b
0/100
(0%)
2/62
(3%)"
2/43
(5%)d
47/50
(94%)c
12/48
(25%)c
47/50
(94%)c
"
Comments
Incidences are
mice with
adenomas or
carcinomas.
Higher
sensitivity in
males during
perinatal
period, in
females during
adulthood.
Incidences are
mice with
adenomas or
carcinomas.
Reference
Vesselinovitch
(1983)
Vesselinovitch et
al. (1975b)
Vesselinovitch et
al. (1979a)
Vesselinovitch et
al. (1979b)
>
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
Dieldrin
DENe
Diethylnitrosamine
Species
(strain)
Mice
(B6C3FO
Rats
(Colworth)
Target
site
liver
liver
esophagus
Age when
first dosed
Control
Weekl
WeekS
Weekl
Control
Week3
Week 6
Week 20
Control
Week 3
Week 6
Week 20
Dose
route,
# doses
None
Gavage,
daily
Diet,
daily
Gavage,
daily until
4 weeks,
then in
diet
Diet (in
drinking
water),
daily
Diet (in
drinking
water),
daily
Dose
Control:
0 ppm
12.5 ug
10 ppm
12.5 ug
10 ppm
Control
16 different
doses
combined'
Control
16 different
doses
combined8
Duration of
exposure
N/A
Weeks 1-4
Weeks 5-90
Weeks 1-90
N/A
From week 3
until death
From week 6
until death
From week 20
until death
N/A
From week 3
until death
From week 6
until death
From week 20
until death
Age at
death
90 weeks
6
months-
3 years
Tumors"
M
1/58
(2%)
3/46
(7%)b
7/60
(12%)b
21/70
(30%)a
F
—
—
"
29/384
(8%)
105/180
(58%)b
714/1440
(50%)b
76/180
(42%)b
0/384
(0%)
77/180
(43%)b
663/1440
(46%)b
88/180
(49%)b
Comments
Highest tumor
rate when dosed
at earlier ages.
Incidents are
rats with
adenomas or
carcinomas.
Reference
Vesselinovitch et
al. (1979b)
Petoetal. (1984)
>
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
DPH
Diphenylhydantoin,
5,5-
Species
(strain)
Rats
(F344/N)
Mice
(B6C3FO
Target
site
liver
liver
Age when
first dosed
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Dose
route,
# doses
Control
Diet,
daily
Control
male
Diet, male
Control
female
Diet,
female
Dose
0 ppm
630 ppm
800 ppm
2,400 ppm
630-800
630-2,400
ppm
0 ppm
210 ppm
100 ppm
300 ppm
210-100
ppm
210-300
ppm
0 ppm
210 ppm
200 ppm
600 ppm
210-200
ppm
210-600
ppm
Duration of
exposure
N/A
Perinatal
through 8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal
through 2 years
Perinatal
through 2 years
N/A
Perinatal
through 8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal
through 2 years
Perinatal
through 2 years
N/A
Perinatal
through 8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal
through 2 years
Perinatal
through 2 years
Age at
death
2 years
2 years
2 years
Tumors"
M
0/50
(0%)
1/50
(2%)"
2/50
(4%)"
4/50
(8%)d
1/49
(2%)"
5/49
(10%)c
29/50
(58%)
33/50
(66%)'*
29/49
(59%)d
26/49
(53%)d
35/49
(71%)d
41/50
(82%)c
F
0/50
(0%)
0/49
(0%)d
1/50
(2%)"
1/50
(2%)"
0/50
(0%)d
0/50
(0%)d
5/48
(10.4%)d
12/49
(24.5%)d
14/49
(28%)c
30/50
(60%)c
16/50
(32%)c
34/50
(68%)c
Comments
In rats, perinatal
exposure ranged
from 63 to 630
ppm, and adult
exposures ranged
from 240 to 2,400
ppm.
In mice, perinatal
exposure ranged
from 21 to 210
ppm. Adult
exposure ranged
from 30 to 300
ppm in males and
60 to 600 ppm in
females.
Tumor incidences
are animals with
adenomas or
carcinomas.
Reference
Chhabra et al.
(1993b)
>
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
ETU
Ethylene thiourea
Species
(strain)
Rats
(F344/N)
Mice
(B6C3FO
Target
site
thyroid
liver
thyroid
Age when
first dosed
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Control
Perinatal
8 weeks
8 weeks
Dose
route,
# doses
Control
Diet,
daily
Control
Diet,
daily
Control
Diet,
daily
Dose
0 ppm
90ppm
83 ppm
250 ppm
90-83 ppm
90-250 ppm
0 ppm
330 ppm
330 ppm
1,000 ppm
330-330
ppm
330-1,000
ppm
0 ppm
330 ppm
330 ppm
1,000 ppm
Duration of
exposure
N/A
Perinatal
through 8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal
through 2 years
Perinatal
through 2 years
N/A
Perinatal
through 8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal
through 2 years
Perinatal
through 2 years
N/A
Perinatal
through 8
weeks
8 weeks-2
years
8 weeks-2
years
Age at
death
2 years
2 years
Tumors"
M
1/49
(2%)
4/49
(8%)d
12/46
(26%)c
37/50
(74%)c
13/50
(26%)c
48/50
(96%)
20/49
(41%)
13/49
(26.5%)d
32/50
(64%)c
46/50
(92%)c
34/49
(69%)c
47/49
(6%)c
1/50
(2%)
1/46
(2%)"
1/49
(2%)"
29/50
(58%)c
F
3/50
(6%)
3/50
(6%)"
7/44
(16%)d
30/49
(61%)c
9/47
(19%)d
37/50
(74%)
4/50
(8%)
5/49
(10%)d
44/50
(88%)c
48/50
(96%)c
46/50
(92%)c
49/50
(98%)c
0/50
(0%)
1/49
(2%)"
2/50
(4%)"
38/50
(76%)c
Comments
Tumor incidences
are animals with
adenomas or
carcinomas.
Reference
Chhabra et al.
(1992)
>
oo
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
ETU
Ethylene thiourea
(continued)
Species
(strain)
Target
site
pituitary
Age when
first dosed
Perinatal
Perinatal
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Dose
route,
# doses
Control
Diet,
daily
Dose
330-330
ppm
330-1,000
ppm
0 ppm
330 ppm
330 ppm
1,000 ppm
330-330
ppm
330-1,000
ppm
Duration of
exposure
Perinatal
through 2 years
Perinatal
through 2 years
N/A
Perinatal
through 8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal
through 2 years
Perinatal
through 2 years
Age at
death
Tumors"
M
2/48
(4%)"
35/49
(71%)c
0/44
(0%)
0/42
(0%)d
0/42
(0%)d
8/41
(19.5%)c
0/45
(0%)d
4/39
(10%)d
F
10/49
(20%)c
38/50
(76%)c
11/47
(23%)
11/48
(23%)d
19/49
(39%)d
26/49
(53%)c
26/47
(55%)c
24/47
(51%)c
Comments
Reference
>
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
3-Methylcholanthrene
(formerly known as 20-
methylcholanthrene)
Species
(strain)
Mice
(Albino)
Target
site
liver
lung
fore-
stomach
skin
Age
when
first
dosed
Control
8 days
90 days
Control
8 days
90 days
Control
8 days
90 days
Control
8 days
90 days
Dose route,
# doses
gavage, 3x
per week
Dose
NA
0.25 mg/g
0.25 mg/g
NA
0.25 mg/g
0.25 mg/g
NA
0.25 mg/g
0.25 mg/g
NA
0.25 mg/g
0.25 mg/g
Duration of
exposure
NA
10x
10x
NA
10x
10x
NA
10x
10x
NA
10x
10x
Age at death
M
475 days
311 days
330 days
475 days
311 days
330 days
475 days
311 days
330 days
475 days
311 days
330 days
F
480 days
321 days
366 days
480 days
321 days
366 days
480 days
321 days
366 days
480 days
321 days
366 days
Tumor incidence
M
3/39
(7.7%)
21/25
(84%)b
1/26
(3.8%)b
17/39
(43.6%)
25/25
(100%)b
25/26
(96.2%)b
0/39
(0%)
12/25
(48%)b
13/26
(50%)b
0/39
(0%)
4/25
(16%)b
1/26
(3.8%)b
F
0/36
(0%)
7/30
(23.3%)b
0/29
(0%)d
14/36
(38.9%)
28/30
(93.3%)b
27/29
(93.1%)b
0/36
(0%)
12/30
(40%)b
8/29
(27.6%)b
0/36
(0%)
4/30
(13.3%)b
1/25
(4%)b
Reference
Klein (1959)
>
o
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
PBBs
Polybrominated
biphenyls
Species
(strain)
Rats (F344/N)
Mice (B6C3FO
Target
site
liver8
Mono-
nuclear
cell
leukemia
(MCL)
liver8
Age when
first dosed
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Control
Perinatal
8 weeks
8 weeks
Perinatal
Perinatal
Dose
route,
# doses
Control
Diet
Control
Diet
Control
Diet
Dose
0 ppm
10 ppm
10 ppm
30 ppm
10-10 ppm
10-30 ppm
0 ppm
10 ppm
10 ppm
30 ppm
10-10 ppm
10-30 ppm
0 ppm
30 ppm
10 ppm
30 ppm
10 ppm
30-30 ppm
Duration of
exposure
N/A
Perinatal-8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal-2
years
Perinatal-2
years
N/A
Perinatal-8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal-2
years
Perinatal-2
years
N/A
Perinatal-8
weeks
8 weeks-2
years
8 weeks-2
years
Perinatal-2
years
Perinatal-2
years
Age at
death
2 years
2 years
2 years
Tumors"
M
1/50
(2%)
5/50
(10%)d
12/49
(24%)c
41/50
(82%)c
16/50
(32%)c
41/50
(82%)c
25/50
(50%)
31/50
(62%)d
33/50
(66%)c
31/50
(62%)d
37/50
(74%)c
37/50
(74%)c
16/50
(32%)
40/50
(80%)c
48/49
(98%)c
48/50
(96%)c
46/49
(94%)c
50/50
(100%)c
F
0/50
(0%)
0/50
(0%)d
12/50
(24%)c
39/50
(78%)c
39/50
(78%)c
47/50
(94%)c
14/50
(28%)
13/50
(26%)d
22/50
(44%)d
23/50
(46%)c
27/50
(54%)c
25/50
(50%)c
5/50
(10%)
21/50
(42%)c
42/50
(84%)c
47/48
(98%)c
44/50
(88%)c
47/47
(100%)c
Comments
Findings suggest
that combined
perinatal and adult
exposure increases
PBB-related
hepatocellular
carcinogenicity
relative to adult-
only exposure in
mice and female
rats.
Apparent
association
between
increasing
incidences of
MCL and
exposure to PBB
in male and
female rats.
Tumor incidences
are animals with
adenomas or
carcinomas.
Reference
Chhabra et al.
(1993a)
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
Safrole
Urethane
Species
(strain)
Mice
(B6C3FO
Mice (B6AFi/J)
Target
site
liver
liver
Age when
first dosed
Control
Day 12 of
gestation
Newborn
At weaning
Day 12 of
gestation
Day 12 of
gestation
1 week
1 week
4 weeks
Dose
route,
# doses
None
Gavage, to
mothers
Gavage, to
mothers, on
alternate
days
Gavage, to
offspring, 2x
weekly
Gavage, to
mothers,
alternate
days
Gavage, to
mothers,
alternate
days until
weaning;
Gavage, to
offspring, 2x
weekly
gavage
Dose
None
120 ug/g
body weight
120 ug/g
body weight
120 ug/g
body weight
120 ug/g
body weight
120 ug/g
body weight
2.5 mg/pup
2. 5 mg/pup
2.5 mg/pup
Duration of
exposure
N/A
4x (days 12,
14, 16, 18)
From birth until
weaning
From weaning
until 90 weeks
From gestation
until weaning
From gestation
until 90 weeks
lx
16x
(lx at 1 week;
3 x weekly for 5
weeks
beginning at 4
wks of age)
15x
(3 x weekly for
5 weeks
beginning at 4
weeks of age)
Age at
death
90 weeks
39-40
weeks
39 weeks
41 weeks
Tumors"
M
3/100
(3%)
2/61
(3%)"
28/83
(34%)c
4/35
(ll%)d
22/68
(32%)b
19/37
(51%)b
F
0/100
(0%)
0/65
(0%)d
2/80
(3%)"
22/36
(61%)c
1/72
(1%)"
37/46
(80%)b
Tumor incidence3
M
12/37
(33%)"
11/33
(33%)b
0/37
(0%)b
F
0/40
(0%)b
0/31
(0%)b
0/31
(0%)b
Comments
Highest tumor rate
in males due to
preweamng
treatment.
Highest tumor rate
in females due to
susceptibility in
adulthood.
Tumor incidences
are mice with
adenomas or
carcinomas.
No tumor data for
controls.
Reference
Vesselinovitch
etal. (1979b)
Klein (1966)
>
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
VC
Vinyl chloride
Species
(strain)
Rats (Sprague-
Dawley)
Target
site
liver
angio-
sarcoma
zymbal
gland
leukemia
nephro-
blastoma
Age when
first dosed
Control
Newborn
Week 13
Control
Newborn
Week 13
Control
Newborn
Week 13
Control
Newborn
Dose
route,
# doses
Control
Inhalation
Control
Inhalation
Control
Inhalation
Control
Inhalation
Dose
0 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
0 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
0 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
0 ppm
6,000 ppm
10,000 ppm
Duration of
exposure
N/A
4 hrs/day,
5 days/wk,
5 weeks
4 hrs/day,
5 days/wk, 52
weeks
N/A
4 hrs/day,
5 days/wk,
5 weeks
4 hrs/day,
5 days/wk, 52
weeks
N/A
4 hrs/day,
5 days/wk,
5 weeks
4 hrs/day,
5 days/wk, 52
weeks
N/A
4 hrs/day,
5 days/wk,
5 weeks
Age at
death
135
weeks
124
weeks
135
weeks
135
weeks
124
weeks
135
weeks
135
weeks
124
weeks
135
weeks
135
weeks
124
weeks
Tumors"
M
0/22
(0%)
5/18
(28%)b
6/24
(25%)b
3/17
(18%)b
3/21
(14%)b
0/28
(0%)
1/12
(8%)b
1/17
(6%)b
3/29
(10%)b
10/30
(33%)b
0/27
(0%)
N/A
2/6
(33%)b
N/A
0/27
(0%)b
0/22
(0%)
0/15
(0%)b
0/19
(0%)b
F
0/29
(0%)
12/24
(50%)b
9/20
(45%)b
10/25
(40%)b
4/25
(16%)b
0/29
(0%)
1/17
(6%)b
0/17
(0%)b
4/30
(13%)b
6/30
(20%)b
1/29
(3%)
1/7
(14%)b
0/15
(0%)b
0/29
(0%)b
2/29
(7%)b
0/29
(0%)
0/21
(0%)b
0/17
(0%)b
Comments
Higher tumor risk
when exposed at
birth, higher for
females.
Reference
Maltoni et al.
(1984)
>
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
VC
Vinyl chloride
(continued)
Species
(strain)
Target
site
angio-
sarcomas:
other sites
angiomas
and
fibromas:
other sites
hepatoma
Age when
first dosed
Week 13
Control
Newborn
Week 13
Control
Newborn
Week 13
Control
Newborn
Week 13
Dose
route,
# doses
Control
Inhalation
Control
Inhalation
Control
Inhalation
Dose
6,000 ppm
10,000 ppm
0 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
0 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
0 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
Duration of
exposure
4 hrs/day,
5 days/wk, 52
weeks
N/A
4 hrs/day,
5 days/wk,
5 weeks
4 hrs/day,
5 days/wk, 52
weeks
N/A
4 hrs/day,
5 days/wk,
5 weeks
4 hrs/day,
5 days/wk, 52
weeks
N/A
4 hrs/day,
5 days/wk,
5 weeks
4 hrs/day,
5 days/wk, 52
weeks
Age at
death
135
weeks
135
weeks
124
weeks
135
weeks
135
weeks
124
weeks
135
weeks
135
weeks
124
weeks
135
weeks
Tumors"
M
4/18
(22%)b
3/21
(14%)b
0/29
(0%)
1/15
(7%)b
0/19
(0%)
1/29
(3%)"
2/30
(7%)b
0/28
(0%)
1/15
(7%)"
2/19
(ll%)b
2/29
(7%)b
2/29
(7%)"
0/19
(0%)
9/18
(50%)b
13/24
(54%)b
0/10
(0%)b
1/8
(13%)b
F
1/26
(4%)b
2/25
(8%)b
0/29
(0%)
0/21
(0%)b
0/17
(0%)b
2/30
(7%)b
1/30
(3%)b
2/29
(7%)b
0/21
(0%)b
1/17
(6%)b
2/30
(7%)b
1/29
(3%)b
0/28
(0%)
11/24
(46%)b
7/20
(35%)b
1/17
(6%)b
0/16
(0%)b
Comments
Reference
>
-------
Table 2. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult repeated exposures (continued)
Chemical
VC
Vinyl chloride
(continued)
Species
(strain)
Target site
skin
carcinomas
neuro-
blastoma
Age when
first dosed
Control
Newborn
Week 13
Control
Newborn
Week 13
Dose
route,
# doses
Control
Inhalation
Control
Inhalation
Dose
0 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
0 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
Duration of
exposure
N/A
4 hrs/day,
5 days/wk,
5 weeks
4 hrs/day,
5 days/wk, 52
weeks
N/A
4 hrs/day,
5 days/wk,
5 weeks
4 hrs/day,
5 days/wk, 52
weeks
Age at
death
135
weeks
124
weeks
135
weeks
135
weeks
124
weeks
135
weeks
Tumors"
M
0/20
(0%)
1/10
(10%)b
1/16
(6%)"
0/15
(0%)b
2/13
(15%)b
0/22
(0%)
0/18
(0%)b
0/22
(0%)b
2/21
(10%)b
2/22
(9%)b
F
1/29
(3%)
1/14
(7%)b
0/15
(0%)b
2/19
(11%)"
1/21
(5%)b
0/29
(0%)
0/29
(0%)b
0/19
(0%)b
1/27
(4%)b
5/26
(19%)b
Comments
Reference
>
a Where not delineated by gender, data combined by study authors or gender not specified. Where percentages only are given, number of subjects not specified.
bNot evaluated by authors.
0 Significant compared with controls.
dEvaluated but not significant compared with controls.
e Reported as NDEA (N-nitrosodiethylamine) in the original document.
f Results from each dose are not available.
8 Tumors were adenomas or carcinomas.
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure
Chemical
BaP
Benzo[a]pyrene
Species
(strain)
Mice
(B6C3FO
Mice
(C3AFO
Target
site
liver
liver
Age when
first dosed
Control
Day 1
Day 15
Day 42
Control
Day 1
Day 15
Dose
route,
# doses
Control
i.p.
i.p.
i.p.
Control
i.p.
i.p.
Dose
None
75 ug/g
body weight
150 ug/g
body weight
75 ng/g
body weight
150 ug/g
body weight
75 ng/g
body weight
150 ug/g
body weight
None
75 Hg/g
body weight
150 ug/g
body weight
75ug/g
body weight
Duration of
exposure
N/A
lx
lx
lx
lx
lx
lx
N/A
lx
lx
lx
Age at
death
142 weeks
86 weeks
(m)
129 weeks
(f)
81 weeks
(m)
121 weeks
(f)
93 weeks
(m)
1 16 weeks
(f)
81 weeks
(m)
90 weeks (f)
108
weeks(m)
87 weeks
(m)
142 weeks
80 weeks
(m)
91 weeks (f)
69 weeks
(m)
701 weeks
(f)
90 weeks
(m)
102 weeks
(f)
Tumors3
M
7/100
(7%)
26/47
(55%)b
51/63
(81%)b
36/60
(60%)b
32/55
(58%)b
7/55
(13%)b
4/47
(9%)b
8/100
(8%)
21/62
(34%)b
24/52
(46%)b
15/56
(27%)b
F
1/100
(1%)
3/45
(7%)b
8/45
(18%)b
4/55
(7%)b
4/55
(7%)b
0/47
(0%)b
0/46
(0%)b
1/100
(1%)
1/45
(2%)b
1/56
(2%)b
1/49
(2%)b
Comments
In general, hepatomas
developed with
significantly higher
incidence (p<0.01) in
mice that were treated
within 24 hours of birth
or at 15 days of age
than they did in
similarly treated
animals at 42 days of
age.
+ higher for males.
+ higher for males.
"Age at death" is the
average age at which
tumors were observed.
Reference
Vesselinovitch
etal. (1975a)
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
BaP
Benzo[a]pyrene
(continued)
Species
(strain)
Mice
(B6C3FO
Target
site
lung
Age when
first dosed
Day 42
Control
Day 1
Day 15
Day 42
Dose
route,
# doses
i.p.
Control
i.p.
i.p.
i.p.
Dose
150 ug/g
body weight
75 ug/g
body weight
150 jig/g
body weight
Control
75 ug/g
body weight
150 ug/g
body weight
75 ug/g
body weight
150 ug/g
body weight
75 Ug/g
body weight
150 jig/g
body weight
Duration of
exposure
lx
lx
lx
N/A
lx
lx
lx
lx
lx
lx
Age at
death
77 weeks
(m)
62 weeks (f)
79 weeks
(m)
142 weeks
103 weeks
(m)
126 weeks
(f)
84 weeks
(m)
1 12 weeks
(f)
103 weeks
(m)
122 weeks
(f)
82 weeks
(m)
101 weeks
(f)
1 19 weeks
(m)
131 weeks
(f)
95 weeks
(m)
118 weeks
(f)
Tumors"
M
12/53
(23%)b
0/30
(0%)b
1/32
(3%)c
13/100
(13%)
20/47
(43%)"
37/63
(59%)b
15/60
(25%)b
20/55
(36%)"
20/55
(36%)b
18/47
(38%)b
F
1/57
(2%)b
0/32
(0%)b
0/40
(0%)b
9/100
(9%)
22/45
(49%)b
28/45
(62%)b
18/55
(33%)b
18/45
(40%)b
12/47
(26%)b
8/46
(17%)b
Comments
Both sexes developed
lung tumors with higher
incidence when treated
with BaP at birth than at
1 5 or 42 days of age
(p<0.05).
Reference
>
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
BaP
Benzo[a]pyrene
(continued)
DBA
Dibenz anthracene
Species
(strain)
Mice
(C3AFO
Mice
(Caracul x P
stock)
Target
site
lung
lung
Age when
first dosed
Control
Day 1
Day 15
Day 42
Control
Day 1
2 months
Dose
route,
# doses
Control
i.p.
i.p.
i.p.
Control
i.p.
s.c.
Dose
None
75 ng/g
body weight
150 ug/g
body weight
75 ug/g
body weight
150 ug/g
body weight
75 ng/g
body weight
150 ug/g
body weight
None
4 mg per
cm3 vehicle
4 mg per
cm3 vehicle
Duration of
exposure
N/A
lx
lx
lx
lx
lx
lx
N/A
lx
lx
Age at
death
142 weeks
78 weeks
(m)
82 weeks (f)
70 weeks
(m)
73 weeks (f)
87 weeks
(m)
98 weeks (f)
75 weeks
(m)
79 weeks (f)
91 weeks
(m)
93 weeks (f)
85 weeks
(m)
83 weeks (f)
228 days
181 days
189 days
Tumors"
M
60/100
(60%)
58/62
(93%)b
48/52
(92%)b
52/56
(93%)b
50/53
(94%)b
28/30
(93%)b
28/32
(87%)b
F
50/100
(50%)
42/45
(93%)b
52/56
(93%)b
46/49
(94%)b
52/57
(91%)b
28/32
(87%)b
36/40
(90%)b
1/31
(3.2%)
24/24
(100%)b
2/29
(6.9%)b
Comments
Of the two mouse
strains tested, C3AFi
mice developed
significantly more
tumors than did the
B6C3Fi mice
(p<0.001).
Reference
Vesselinovitch et
al. (1975a)
Law (1940)
>
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
DEN
Diethylnitrosamine
Species
(strain)
Mice
(B6C3FO
Target
site
liver
Age when
first dosed
Control
Day 1
Day 15
Day 42
Dose
route,
# doses
Control
i.p. (3-, 6-
and 6-day
intervals)
Dose
Vehicle
(0.01 mL
trioctanoin/g
body weight)
1-5 Hg/g
body weight
3 ug/g body
weight
1-5 Hg/g
body weight
3 ug/g body
weight
1-5 Hg/g
body weight
3 ug/g body
weight
Duration of
exposure
4x
4x
4x
4x
4x
4x
4x
Age at
death
142
weeks
(m)
137
weeks (f)
67 weeks
(m)
90 weeks
(f)
65 weeks
(m)
80 weeks
(f)
86 weeks
(m)
117
weeks (f)
76 weeks
(m)
96 weeks
(f)
117
weeks
(m)
135
weeks (f)
123
weeks
(m)
133
weeks (f)
Tumors"
M
7/98
(7%)
37/51
(73%)b
40/58
(69%)b
41/57
(72%)b
48/69
(70%)b
9/49
(18%)b
6/38
(16%)b
F
1/100
(1%)
45/64
(70%)b
44/65
(68%)b
40/71
(56%)b
46/62
(74%)b
1/47
(2%)b
4/57
(7%)b
Comments
Animals treated as
newborns and infants
developed significantly
more liver tumors than
animals that were
treated as young adults.
Newborns and infant
females developed liver
tumors at a later age
than similarly treated
males.
Incidences for
malignant tumors only.
Reference
Vesselinovitch et
al. (1984)
>
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
DEN
Diethylnitrosamine
(continued)
Species
(strain)
Mice
(C3AFO
Mice
(B6C3FO
Target
site
liver
lung
Age
when
first
dosed
Control
Day 1
Day 15
Day 42
Control
Dose
route,
# doses
Control
i.p. (3-, 6-
and 6-day
intervals)
Control
Dose
Vehicle (0.1
trioctanoin/g
body weight)
1-5 Hg/g
body weight
3 ug/g body
weight
1-5 Hg/g
body weight
3 ug/g body
weight
1-5 Ug/g
body weight
3 ug/g body
weight
Vehicle (0.1
trioctanoin/g
body weight)
Duration of
exposure
4x
4x
4x
4x
4x
4x
4x
4x
Age at
death
123
weeks
(m)
131weeks
(f)
64 weeks
(m)
84 weeks
(f)
59 weeks
(m)
76 weeks
(f)
82 weeks
(m)
102
weeks (f)
74 weeks
(m)
94 weeks
(f)
105
weeks
(m)
106
weeks (f)
105
weeks
(m)
103
weeks (f)
142
weeks
(m)
137
weeks (f)
Tumors"
M
8/99
(8%)
23/32
(72%)b
39/58
(67%)b
22/46
(48%)b
35/54
(65%)b
12/56
(22%)b
9/57
(16%)b
13/98
(13%)
F
1/97
(1%)
11/39
(28%)b
26/50
(52%)b
8/65
(12%)b
22/62
(35%)b
0/53
(0%)b
0/56
(0%)b
9/100
(9%)
Comments
Highest tumor rate
when dosed at early
ages.
Newborns and infant
females developed liver
tumors at a lower
incidence than similarly
treated males.
+ higher for males.
The mice treated as
newborns showed lung
tumors earlier than
animals exposed at
other times. It is not
known whether this was
due to actual earlier
emergence of tumors or
Reference
Vesselinovitch et
al. (1984)
to
o
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
DEN
Diethylnitrosamine
(continued)
Species
(strain)
Mice
(C3AFO
Target
site
lung
Age
when
first
dosed
Day 1
Day 15
Day 42
Control
Day 1
Dose
route,
# doses
i.p. (3-, 6-
and 6-day
intervals)
Control
i.p. (3-, 6-
and 6-day
intervals)
Dose
1-5 ug/g
body weight
3 ug/g body
weight
1-5 Ug/g
body weight
3 ug/g body
weight
1-5 Ug/g
body weight
3 ug/g body
weight
Vehicle (0.1
trioctanoin/g
body weight)
1-5 Ug/g
body weight
3 ug/g body
weight
Duration of
exposure
4x
4x
4x
4x
4x
4x
4x
4x
4x
Age at
death
70 weeks
(m)
91 weeks
68 weeks
(m)
81 weeks
(f)
87 weeks
(m)
115
weeks (f)
77 weeks
(m)
97 weeks
(f)
123
weeks
(m)
129
weeks (f)
121
weeks
(m)
127
weeks (f)
142
weeks
(m)
137weeks
(f)
65 weeks
(m)
84 weeks
(f)
59 weeks
(m)
76 weeks
(f)
Tumors"
M
29/51
(57%)b
34/58
(59%)b
51/57
(89%)b
51/69
(74%)b
38/49
(78%)b
33/38
(87%)b
60/99
(61%)
30/32
(94%)b
49/58
(84%)b
F
49/64
(77%)b
42/65
(65%)b
61/71
(86%)b
53/62
(85%)b
38/47
(81%)b
43/57
(75%)b
50/97
(52%)
38/39
(97%)b
46/50
(92%)b
Comments
to their earlier detection
caused by shorter
survival.
Of the two strains,
C3AFi mice developed
lung tumors with a
higher incidence and
multiplicity than
B6C3Fi hybrids.
Reference
>
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
DEN
Diethylnitrosamine
(continued)
Species
(strain)
Mice
(B6C3FO
Target
site
liver
Age
when
first
dosed
Day 15
Day 42
Control
Gestation
day 18
Day 15
Day 42
Day 1
Day 15
Dose
route,
# doses
Control
i.p.
i.p. (3-, 6-
and 6-day
intervals)
i.p.
i.p.
Dose
1-5 Hg/g
body weight
3 ug/g body
weight
1-5 Hg/g
body weight
3 ug/g body
weight
None
1-5 Ug/g
body weight
1-5 Ug/g
body weight
1-5 Ug/g
body weight
1-5 Ug/g
body weight
5 ug/g body
weight
10 ug/g
body weight
1-5 Ug/g
body weight
5 ug/g body
weight
Duration of
exposure
4x
4x
4x
4x
N/A
lx
4x
4x
lx
lx
lx
lx
lx
Age at
death
80 weeks
(m)
101
weeks (f)
74 weeks
(m)
92 weeks
(f)
104
weeks
(m)
110
weeks (f)
101
weeks
(m)
102
weeks (f)
90 weeks
73 weeks
Tumors"
M
42/46
(91%)b
50/54
(93%)b
55/56
(98%)b
56/57
(98%)b
1/98
(1%)
2/50
(4%)b
47/51
(92%)b
13/49
(26%)b
15/59
(25%)b
29/45
(64%)b
24/25
(96%)b
13/24
(54%)b
40/54
(74%)b
F
61/65
(94%)b
57/62
(92%)b
52/53
(98%)b
54/56
(96%)b
0/96
(0%)
1/51
(2%)b
60/64
(94%)b
3/47
(6%)b
—
—
—
—
—
Comments
Infant animals of both
sexes (Day 15) were
more sensitive than
similarly exposed
adults.
At the 1.5-jig dose
level, 1 -day-old mice
developed significantly
fewer liver tumors than
similarly treated infants
(Day 15)(p<0.025).
Tumor incidence in
treated groups versus
controls was not
evaluated.
Reference
Vesselinovitch
and Mihailovich
(1983)
Vesselinovitch et
al. (1979a)
to
to
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
DEN
Diethylnitrosamine
(continued)
DMBA
Dimethyl-
benz[a]anthracene
Species
(strain)
Rats
(Sprague-
Dawley)
Rats
(Wistar)
Rats (Wistar,
castrated)
Target
site
mammary
adeno-
sarcoma
mammary
carcinoma11
mammary
carcinoma
Age
when
first
dosed
Day 20
Day 30
Day 40
Day 46
Day 55
Day 70
Day 140
Day 180
Control
5-8
weeks
Control
26 weeks
< Week 2
Week 5-8
Week 26
Week 5-8
Week 26
Dose
route,
# doses
Gavage
Control
Control
Gavage
Gavage
Dose
lOug/g
body weight
10 mg/100 g
body weight
10 mg/100 g
body weight
10 mg/100 g
body weight
10 mg/100 g
body weight
10 mg/100 g
body weight
10 mg/100 g
body weight
10 mg/100 g
body weight
10 mg/100 g
body weight
None
None
0.5-l.Omg
15 mg
15 mg
15 mg
15 mg
Duration of
exposure
lx
lx
lx
lx
lx
lx
lx
lx
lx
N/A
N/A
lx
lx
lx
lx
lx
Age at
death
Week 25
Week 26
Week 27
Week 28
Week 29
Week 32
Week 42
Week 47
17
months
20
months
Week 40-
56
Week 14-
55
Week 32-
73
Week 14-
55
Week 32-
73
Tumors"
M
25/25
(100%)b
"
—
—
—
"
—
—
—
0/22
(0%)
0/31
(0%)
0/23
(0%)b
0/23
(0%)b
0/34
(0%)b
0/21
(0%)b
0/33
(0%)b
F
3/6
(50%)b
14/15
(93%)b
8/9
(89%)b
8/8
(100%)b
33/34
(97%)b
5/8
(63%)b
10/15
(67%)b
14/26
(54%)b
0/25
(0%)
2/20
(10%)
4/50
(8%)b
14/25
(56%)b
4/26
(15%)b
0/22
(0%)b
0/26
(0%)b
Comments
36 of 42 (86%) animals
dosed at age 20 days
died soon after.
Highest number of
tumors per animal was
in the 46-day group,
with decreasing
numbers in the older
animals.
Animals were sacrificed
22 weeks after
treatment.
Highest tumor rate in
females exposed at 5-8
weeks.
Animals were observed
for 16 months following
treatment.
Reference
Russo et al. (1979)
Meranze et al.
(1969)
to
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
DMBA
Dimethyl-
benz[a]anthracene
(continued)
Species
(strain)
Rats
(Wistar)
Mice
(BALB/c)
Mice (Swiss)
Target
site
Total tumors
lung
lymphoma
Age
when
first
dosed
Control
5-8
weeks
Control
26 weeks
< Week 2
Week 5-8
Week 26
Control:
Day 1
Day 1
Week 2-3
(suckling)
Adulte
Control
Day 1
Day 1
Week 8
Dose
route,
# doses
Control
Control
Gavage
Control
s.c.
s.c.
s.c.
s.c.
s.c.
s.c.
s.c.
Control
i.p.
s.c.
s.c.
Dose
None
None
0.5-1.0 mg
15 mg
15 mg
Aqueous
gelatine
15 ug
15 ug
30 ug
(60 ug total)
15 Ug
30 ug
(60 ug total)
30 ug
(180 ug
total)
None
30-40 ug
30-40 ug
900 ug
Duration of
exposure
N/A
N/A
lx
lx
lx
lx
lx
lx
2x
lx
2x
6x
N/A
lx
lx
lx
Age at
death
17
months
20
months
Week 40-
56
Week 14-
55
Week 32-
73
40 weeks
40 weeks'
42-43
weeks
42-43
weeks
48-49
weeks
48-49
weeks
48-49
weeks
31-52
weeks
13-33
weeks
12-27
weeks
30 weeks
Tumors"
M
0/22
(0%)
2/31
(6%)
16/23
(70%)b
7/23
(30%)b
12/34
(35%)b
0/12
(0%)
14/14
(100%)b
12/23
(52%)b
14/14
(100%)b
6/12
(50%)b
9/10
(90%)b
12/12
(100%)b
F
0/25
(0%)
5/20
(25%)
36/50
(72%)b
16/25
(64%)b
13/26
(50%)b
7/23
(30%)
24/24
(100%)b
16/22
(73%)b
24/24
(100%)b
15/33
(45%)b
21/23
(91%)b
13/13
(100%)b
3/408
(0.7%)
6/31
(19%)b
8/27
(30%)b
1/13
(8%)b
Comments
Total tumors includes
leukemia.
15 ug DMBA gave rise
to a significantly greater
incidence of lung
tumors when
administered to
newborn mice than to
suckling or young
adults.
Higher tumor rates at
younger age of
exposure.
Only one treatment
group was exposed i.p.;
others were exposed by
s.c. injection..
Reference
Walters (1966)
Pietraetal. (1961)
to
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
DMBA
Dimethyl-
benz[a]anthracene
(continued)
DMN
Dimethyl-
nitrosamine
Species
(strain)
Mice (Swiss)
Rats
(Wistar)
Rats
(Wistar)
Target
site
lung
kidney
carcinoma
kidney
adenoma
Age
when
first
dosed
Control
Day 1
Day 1
Week 8
Day 1
Day 21
Month 1
Month 1.5
Month 2
Month 3
Month 4
Month 5
Day 1
Day 21
Month 1
Month 1.5
Month 2
Month 3
Month 4
Month 5
Dose
route,
# doses
Control
i.p.
s.c.
s.c.
i.p.
i.p.
Dose
None
30-40 ug
30-40 ug
900 jig
20 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
20 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
Duration of
exposure
N/A
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
31-52
weeks
13-33
weeks
12-27
weeks
30 weeks
>5
months
>5
months
Tumors"
M
F
4/408
(0.9%)
24/31
(77%)b
23/27
(85%)b
2/
13
1/33 (3)b
5/39 (13)b
2/33 (6)b
1/28 (4)b
1/26 (4)b
10/27 (37)b
7/32
(22)b
0/14 (0)b
1/33 (3)b
13/39 (33)b
ll/33(33)b
13/28 (48)b
1 1/26 (42)b
18/27(67)b
17/32 (53)b
6/14 (43)b
Comments
In the neonatal group,
the dose was reduced to
20 mg/kg to achieve
approximately
equivalent numbers of
survivors.
No control group.
Reference
Hard (1979)
to
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
DMN
Dimethyl-
nitrosamine
(continued)
Species
(strain)
Rats
(Wistar)
Rats
(Wistar)
Rats
(Wistar)
Target
site
kidney
mesenchymal
tumors
kidney
cortical
epithelial
tumors
Total tumors
Age
when
first
dosed
Day 1
Day 21
Month 1
Month 1.5
Month 2
Month 3
Month 4
Month 5
Day 1
Day 21
Month 1
Month 1.5
Month 2
Month 3
Month 4
Month 5
Day 1
Day 21
Month 1
Month 1.5
Month 2
Month 3
Month 4
Month 5
Dose
route,
# doses
i.p.
i.p.
i.p.
Dose
20 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
20 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
20 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
30 mg/kg
Duration of
exposure
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
>5
months
>5
months
>5
months
Tumors"
M F
8/33 (24)b
18/39(46)b
23/33 (70)b
5/28 (19)b
2/26 (8)b
3/27 (ll)b
7/32 (22)b
0/14 (0)b
2/33 (6)b
16/39 (41)b
12/33 (36)b
14/28 (52)b
ll/26(42)b
18/27(67)b
21/32(66)b
6/14 (43)b
11/33 (33)b
25/39 (64)b
25/33 (76)b
17/28 (63)b
13/26 (50)b
18/27(67)b
22/32 (69)b
7/14 (50)b
Comments
Mesenchymal tumors
were most frequent in
the three youngest age
groups (z test,
p< 0.001).
Reference
Hard (1979)
to
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
ENU
Ethylnitrosourea
Species
(strain)
Rats
Mice
(B6C3FO
Rats
(Wistar)
Target
site
nervous
system
liver
nerve tissue
Age
when
first
dosed
Day 1
Day 30
Control
Gestation
day 18
Day 15
Day 42
Control
Gestation
day 16
Day 1
Weekl
Week 2
Week3
Week 4
Dose
route,
# doses
Injection
Injection
Control
i.p.
Control
i.p.
s.c.
Dose
20 mg/kg
20 mg/kg
None
60 ug/g
body weight
60 ug/g
body weight
60 ug/g
body weight
None
40 mg/kg
40 mg/kg
40 mg/kg
40 mg/kg
40 mg/kg
40 mg/kg
Duration of
exposure
lx
lx
N/A
lx
lx
lx
N/A
lx
lx
lx
lx
lx
lx
Age at
death
90 weeks
4-7
months
Tumors"
M
F
100%b
61%b
1/98
(1%)
28/52
(54%)b
41/50
(82%)b
10/50
(20%)b
0/16
(0%)
26/26
(100%)b
12/12
(100%)8
12/17
(71%)b
10/14
(71%)b
6/13
(46%)b
8/15
(53%)b
0/96
(0%)
18/49
(37%)b
28/51
(55%)b
5/50
(10%)b
0/10
(0%)
18/18
(100%)b
16/16
(100%)8
18/20
(90%)b
14/18
(78%)b
5/17
(29%)b
2/10
(20%)b
Comments
Susceptibility to neuro-
oncogenic effect
declined with increasing
age.
Both male and female
mice were responsive to
exposure during
prenatal and infant life.
Highest tumor rate seen
when exposed during
gestation or soon after
birth.
Statistically significant
decrease in tumor
incidence with
increasing age of
exposure.
Reference
Maekawa and
Mitsumori (1990)
Vesselinovitch
(1983)
Naitoetal. (1981)
to
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
ENU
Ethylnitrosourea
(continued)
Species
(strain)
Mice
(B6C3FO
Mice
(C3AFO
Mice
(B6C3FO
Target
site
lung
lung
liver
Age
when
first
dosed
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Dose
route,
# doses
i.p.
i.p.
Dose
60 ug/g body
weight
120 ug/gbody
weight
60 ug/g body
weight
120 ug/gbody
weight
60 ug/g body
weight
120ug/gbody
weight
Duration
of
exposure
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
Tumors"
M
49/55
(89%)b
50/55
(91%)b
53/59
(90%)b
36/38
(95%)b
45/49
(92%)b
52/54
(96%)b
46/47
(98%)8
49/49
(100%)8
59/59
(100%)g
63/64
(98%)g
54/56
(96%)g
59/59
(100%)g
50/54
(93%)g
55/56
(98%)g
12/40
(30%)b
29/34
(85%)g
45/48
(94%)g
17/49
(35%)g
F
49/50
(98%)b
47/55
(85%)b
44/51
(86%)b
54/60
(90%)b
43/50
(86%)b
50/57
(88%)b
51/51
(100%)g
57/59
(97%)g
57/57
(100%)g
53/57
(93%)g
50/56
(89%)g
48/48
(100%)g
28/43
(65%)g
33/54
(61%)g
6/39
(15%)b
32/53
(60%)g
29/43
(67%)g
4/50
(8%)g
Comments
Reference
Vesselinovitch et
al. (1974)
oo
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
ENU
Ethylnitrosourea
(continued)
Species
(strain)
Mice
(C3AFi)
Mice
(B6C3FO
Mice
(C3AFO
Target
site
liver
kidney
kidney
Age
when
first
dosed
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Dose
route,
# doses
i.p.
i.p.
i.p.
Dose
60 ug/g body
weight
120ug/gbody
weight
60 ug/g body
weight
120ug/gbody
weight
60 ug/g body
weight
120 ug/gbody
weight
Duration
of
exposure
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
Tumors"
M
42/45
(93%)8
42/50
(84%)8
7/29
(24%)b
55/62
(89%)g
35/45
(78%)g
8/33
(24%)b
11/48
(23%)b
6/41
(15%)b
4/40
(10%)b
10/30
(33%)8
17/37
(46%)8
8/40
(20%)b
7/44
(16%)b
7/41
(17%)b
3/42
(42%)b
4/52
(7%)b
8/35
(23%)b
6/41
(71%)b
F
19/41
(46%)g
19/48
(40%)g
4/50
(8%)b
19/45
(42%)g
15/35
(43%)g
3/33
(9%)b
5/49
(10%)b
7/31
(23%)b
3/37
(8%)b
14/53
(26%)b
19/49
(39%)b
11/39
(28%)b
6/45
(13%)b
8/46
(17%)b
3/43
(7%)b
6/29
(21%)g
12/29
(41%)g
3/39
(8%)b
Comments
Reference
to
VO
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
ENU
Ethylnitrosourea
(continued)
Species
(strain)
Mice
(B6C3F1)
Mice
(C3AFi)
Mice
(B6C3FO
Target
site
Harderian
Harderian
stomach
Age
when
first
dosed
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Dose
route,
# doses
Dose
60 ug/g body
weight
120ug/gbody
weight
60 ug/g body
weight
120ug/gbody
weight
60 ug/g body
weight
120 ug/gbody
weight
Duration
of
exposure
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
Tumors"
M
7/40
(17%)b
10/51
(20%)b
14/50
(28%)b
9/30
(30%)g
15/41
(37%)g
25/48
(52%)g
3/25
(12%)b
1/9
(11%)"
12/48
(25%)"
3/52
(6%)b
6/46
(13%)b
5/29
(17%)b
3/48
(6%)b
10/42
(24%)g
9/51
(18%)g
2/29
(7%)b
10/35
(29%)g
12/53
(23%)g
F
5/43
(12%)b
17/59
(29%)b
14/45
(31%)b
6/52
(12%)b
8/31
(26%)b
14/49
(29%)b
4/35
(ll%)b
6/38
(16%)b
5/33
(15%)b
1/25
(4%)b
2/52
(4%)b
2/11
(18%)b
4/43
(9%)b
7/45
(16%)b
8/36
(22%)b
9/53
(17%)b
12/33
(36%)b
12/50
(24%)b
Comments
Reference
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
ENU
Ethylnitrosourea
(continued)
Species
(strain)
Mice
(C3AFi)
Mice
(B6C3FO
Mice
(C3AFO
Target
site
stomach
malignant
lymphomas
malignant
lymphomas
Age
when
first
dosed
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Day 1
Day 15
Day 42
Dose
route,
# doses
Dose
60 ug/g body
weight
120ug/gbody
weight
60 ug/g body
weight
120ug/gbody
weight
60 ug/g body
weight
120 ug/gbody
weight
Duration
of
exposure
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
Tumors"
M
2/39
(5%)b
7/45
(16%)8
14/55
(25%)g
8/60
(13%)b
16/51
(31%)g
19/48
(40%)g
2/55
(4%)b
3/56
(5%)b
9/59
(15%)b
8/39
(20%)b
14/60
(23%)b
12/59
(20%)b
6/49
(12%)b
3/49
(6%)b
6/60
(10%)b
3/66
(5%)b
10/56
(18%)b
3/49
(6%)b
F
7/45
(16%)b
7/38
(18%)b
7/49
(14%)b
9/44
(20%)b
11/42
(26%)b
13/37
(35%)b
6/52
(12%)8
14/59
(24%)g
17/59
(29%)g
15/65
(23%)g
17/58
(29%)g
14/60
(23%)g
8/49
(16%)g
13/61
(21%)g
9/55
(16%)g
10/58
(17%)g
18/60
(30%)g
13/50
(26%)g
Comments
Reference
>
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
NMU
Methylnitrosourea
Species
(strain)
Mice
(BC3FO
Rats
(Wistar)
Target
site
Total tumors
lung
lympho-
sarcoma
liver
kidney
fore-stomach
mammary
lympho-
sarcoma
kidney (ana-
plastic)
Age
when
first
dosed
Control
Day 1
5
weeks
Day 1
5
weeks
Day 1
5
weeks
Day 1
5
weeks
Day 1
5
weeks
Day 1
5
weeks
Day 1
5
weeks
Day 1
5
weeks
Dose
route,
# doses
Control
i.p.
i.p.
Dose
N/A
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
Duration
of
exposure
N/A
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
Tumor incidence11
M
1/20
(5%)
12/15
(80%)b
10/26
(39%)b
23/39
(59%)b
11/35
(31%)b
10/12
(83%)b
0%b
3/15
(20%)b
2/21
(10%)b
0%b
8/22
(36%)b
0%b
0%b
1/10
(10%)b
2/8
(25%)b
14/18
(78%)b
2/5
(40%)b
F
0%
16/19
(84%)b
10/35
(29%)b
23/45
(51%)b
21/45
(47%)b
1/17
(6%)b
0%c
3/18
(17%)b
0%c
4/17
(24%)b
12/18
(67%)b
4/14
(29%)b
3/5
(60%)b
0%b
1/11
(9%)b
9/13
(69%)b
5/12
(42%)b
Comments
Control mice did not
exhibit tumors in target
sites except a single
hepatoma in a male
control mouse.
Tumor incidence for
control rats was based
on previous
experiments (Delia
Porta et al., 1968) and
was not specifically
reported in this paper.
Reference
Terracini and
Testa (1970)
Terracini and
Testa (1970)
to
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
NMU
Methylnitrosourea
(continued)
Species
(strain)
Mice
(C3Hf/Dp)
Target
site
kidney
(adenoma)
forestomach
intestine
thymus
Age
when
first
dosed
Day 1
5
weeks
Day 1
5
weeks
Day 1
5
weeks
control
Day 1
Day 70
Day 1
Day 21
Day 70
Dose
route,
# doses
i.p.
Dose
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
50 ug/g body
weight
NA
25 ng NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
Duration
of
exposure
lx
lx
lx
lx
lx
lx
NA
lx
lx
lx
lx
lx
Age at
death
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
60 weeks
120 wks"
29 ±8.4
wks
120 wks
(Mf*
100 wks
(F)
16.5 ±0.7
wks
24.5 ±2.5
wks
31.4±4.4
wks
Tumor incidence11
M
3/14
(21%)b
y4
(25%)b
4/14
(29%)b
0%c
3/10
(30%)b
2/4
(50%)b
0/34
(0%)
2/16
(13%)b
0/20
(0%)c
16/24
(67%)b
14/44
(32%)b
9/30
(30%)b
F
2/6
(33%)b
0%b
3/6
(50%)b
0%b
2/2
(100%)b
0%b
0/25
(0%)
5/25
(20%)b
1/20
(5%)b
30/44
(68%)b
18/38
(47%)b
6/41
(15%)b
Comments
Age at death from
thymic lymphoma
reported specifically for
some, but not all, dose
groups.
Control mice were
sacrificed at 120 wks.
Age of death for all
mice in this dose group,
regardless of cancer
type-
Reference
Terracini et al.
(1976)
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
NMU
Methylnitrosourea
(continued)
Species
(strain)
Mice
(C3Hf/Dp)
Target
site
extra-thymic
lymphoma
lung
liver
Age when
first dosed
control
Day 1
Day 70
Day 1
Day 21
Day 70
control
Day 1
Day 70
Day 1
Day 21
Day 70
control
Day 1
Day 70
Day 1
Day 21
Dose
route,
# doses
i.p.
i.p.
i.p.
Dose
NA
25 ug NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
NA
25 ug NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
NA
25 ug NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
Duration of
exposure
NA
lx
lx
lx
lx
lx
NA
lx
lx
lx
lx
lx
NA
lx
lx
lx
lx
Age at death
M
120
weeks
100
weeks
120
weeks
70
weeks
100
weeks
110
weeks
120
weeks
100
weeks
120
weeks
70
weeks
100
weeks
110
weeks
120
weeks
100
weeks
120
weeks
70
weeks
100
weeks
F
120
weeks
90
weeks
100
weeks
80
weeks
90
weeks
90
weeks
120
weeks
90
weeks
100
weeks
80
weeks
90
weeks
90
weeks
120
weeks
90
weeks
100
weeks
80
weeks
90
weeks
Tumor incidence
M
1/34
(3%)
2/16
(13%)b
0/20
(0%)b
0/24
(0%)b
1/44
(2%)"
1/30
(3%)"
4/34
(12%)
7/16
(44%)b
12/20
(60%)b
5/24
(21%)b
23/44
(52%)b
18/30
(60%)b
13/34
(38%)
9/16
(56%)8
12/20
(60%)g
4/24
(17%)g
21/44
(48%)g
F
2/25
(8%)
1/25
(4%)b
0/20
(0%)b
0/44
(0%)b
0/38
(0%)b
0/41
(0%)b
6/25
(24%)
13/25
(52%)b
8/20
(40%)b
11/44
(25%)b
15/38
(39%)b
24/41
(59%)b
1/25
(4%)
2/25
(8%)b
2/20
(10%)b
3/44
(7%)b
1/38
(2.6%)b
Reference
Terracini et al. (1976)
Terracini et al. (1976)
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
NMU
Methylnitrosourea
(continued)
Species
(strain)
Mice
(C3Hf/Dp)
Target
site
stomach
kidney
Age when
first dosed
Day 70
control
Day 1
Day 70
Day 1
Day 21
Day 70
control
Day 1
Day 70
Day 1
Day 21
Day 70
Dose
route,
# doses
i.p.
i.p.
Dose
50 ug NMU/g
body weight
NA
25 ug NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
NA
25 ug NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
Duration of
exposure
lx
NA
lx
lx
lx
lx
lx
NA
lx
lx
lx
lx
lx
Age at death
M
110
weeks
120
weeks
100
weeks
120
weeks
70
weeks
100
weeks
110
weeks
120
weeks
100
weeks
120
weeks
70
weeks
100
weeks
110
weeks
F
90
weeks
120
weeks
90
weeks
100
weeks
80
weeks
90
weeks
90
weeks
120
weeks
90
weeks
100
weeks
80
weeks
90
weeks
90
weeks
Tumor incidence
M
8/30
(27%)8
0/34
(0%)
2/16
(13%)b
3/20
(15%)b
2/24
(8%)b
19/44
(43%)b
8/30
(27%)b
0/34
(0%)
0/16
(0%)b
0/20
(0%)b
0/24
(0%)b
1/44
(2%)"
5/30
(17%)b
F
2/41
(5%)b
5/25
(20%)
10/25
(40%)b
7/20
(35%)b
1/44
(2%)b
9/38
(24%)b
21/41
(51%)b
0/25
(0%)
0/25
(0%)b
0/20
(0%)b
4/44
(9%)b
4/38
(ll%)b
7/41
(17% )b
Reference
Terracini et al. (1976)
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
NMU
Methylnitrosourea
(continued)
Species
(strain)
Mice
(C3Hf/Dp)
Target
site
ovary
mammary
uterus or
vagina
Age when
first dosed
control
Day 1
Day 70
Day 1
Day 21
Day 70
control
Day 1
Day 70
Day 1
Day 21
Day 70
control
Day 1
Day 70
Day 1
Day 21
Day 70
Dose
route,
# doses
i.p.
i.p.
i.p.
Dose
NA
25 ug NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
NA
25 ug NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
NA
25 ug NMU/g
body weight
25 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
50 ug NMU/g
body weight
Duration of
exposure
NA
lx
lx
lx
lx
lx
NA
lx
lx
lx
lx
NA
lx
lx
lx
lx
Age at death
M
120
weeks
100
weeks
120
weeks
70
weeks
100
weeks
110
weeks
120
weeks
100
weeks
120
weeks
70
weeks
100
weeks
110
weeks
120
weeks
100
weeks
120
weeks
70
weeks
100
weeks
110
weeks
F
120
weeks
90
weeks
100
weeks
80
weeks
90
weeks
90
weeks
120
weeks
90
weeks
100
weeks
80
weeks
90
weeks
90
weeks
120
weeks
90
weeks
100
weeks
80
weeks
90
weeks
90
weeks
Tumor incidence
M
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
1/44
(2%)b
NA
NA
NA
NA
NA
NA
F
3/25
(12%)
2/25
(8%)b
4/20
(20%)b
0/44
(0%)b
9/38
(24%)b
16/41
(39%)b
2/25
(8%)
1/25
(4%)b
0/20
(0%)b
0/44
(0%)b
0/38
(0%)b
4/41
(9.8%)b
1/25
(4%)
1/25
(4%)b
6/20
(30%)b
0/44
(0%)b
1/38
(3%)"
7/41
(17%)b
Reference
Terracini et al. (1976)
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
Urethane
Species
(strain)
Mice
(SWR)
Mice
(C3H/f)
Target
site
lung
adenoma
liver
lung
reticular
tissue
Age when
first dosed
Newborn
1 1-22 weeks
Control
Day 1
8-10 weeks
Control
Day 1
8-10 weeks
Control
Day 1
8-10 weeks
Dose
route,
# doses
s.c.
s.c.
Control
i.p.
i.p.
Control
i.p.
i.p.
Control
i.p.
i.p.
Dose
0.18mg/g
body weight
0.25 mg/g
body weight
None
0.8 mg/g
body weight
1 mg/g body
weight
None
0.8 mg/g
body weight
1 mg/g body
weight
None
0.8 mg/g
body weight
1 mg/g body
weight
Duration of
exposure
lx
lx
N/A
lx
lx
N/A
lx
lx
N/A
lx
lx
Age at
death
10 weeks
23-34
weeks
493 days
(m)
553 days
(f)
481 days
(m)
434 days
(f)
321 days
(m)
493 days
(m)
553 days
(f)
401 days
(m)
408 days
(f)
506 days
(m)
493 days
(m)
553 days
(f)
285 days
(m)
343 days
(f)
453 days
(f)
Tumors"
M
F
100%b
0%b
14/97
(14%)
27/30
(90%)8
6/25
(24%)c
0/97
(0%)
14/30
(46%)8
2/25
(8%)c
2/97
(2%)
4/30
(13%)c
0/25
(25%)c
1/77
(1%)
18/39
(46%)8
0/32
(0%)c
0/77
(0%)
19/39
(48%)8
0/32
(0%)c
6/77
(8%)
22/39
(56%)8
4/32
(13%)c
Comments
The average number
of tumors per mouse
increased linearly
with dose.
The number of lung
tumors among the
controls was not
provided.
Reference
Kaye and Trainin
(1966)
Liebeltetal. (1964)
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
Urethane
(continued)
Species
(strain)
Mice
(Swiss)
Mice
(Swiss)
Target
site
leukemia
lung
adenoma
Age when
first dosed
Control
Day 1
Day 5
Day 40
Control
2 weeks
Control
4 weeks
Control
6 weeks
Control
8 weeks
Control
10 weeks
2 weeks
4 weeks
6 weeks
8 weeks
10 weeks
Dose
route,
# doses
Control
s.c.
Control
Control
Control
Control
Control
i.p.
i.p.
i.p.
i.p.
i.p.
Dose
None
2 mg in 0.05
mL aqueous
solution
4 mg in 0.05
mL aqueous
solution
20 mg in 0.1
mL aqueous
solution
None
None
None
None
None
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
Duration of
exposure
N/A
lx
lx
lx
N/A
N/A
N/A
N/A
N/A
lx
lx
lx
lx
lx
Age at
death
8-10
months
9 weeks
1 1 weeks
13 weeks
15 weeks
17 weeks
9 weeks
1 1 weeks
13 weeks
15 weeks
17 weeks
Tumors"
M
F
1%
13/60
(22%)b
7/39
(18%)b
2/63
(3%)b
0/15
(0%)
0/14
(0%)
1/15
(7%)
2/15
(13%)
0/15
(0%)
24/24
(100%)b
23/25
(92%)b
22/25
(88%)b
21/25
(84%)b
19/25
(76%)b
—
—
—
—
—
—
—
—
—
—
Comments
Highest tumor rates
when dosed at birth.
Exposure to
newborns was
followed by 21.6%
leukemia, occurring
at a mean age of 105
days.
The proportion of
animals with
adenomas decreased
steadily with age of
exposure.
Reference
Fiore-Donati et al.
(1962)
Rogers (1951)
oo
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
Urethane
(continued)
Species
(strain)
Mice
(Swiss)
Target
site
lung
adenoma
Age when
first dosed
3 weeks
8 weeks
Dose
route,
# doses
i.p.
i.p.
Dose
0.25 mg/g
body weight
0.5 mg/g
body weight
1 mg/g body
weight
0.25 mg/g
body weight
0.5 mg/g
body weight
1 mg/g body
weight
Duration of
exposure
lx
lx
lx
lx
lx
lx
Age at
death
12 weeks
12 weeks
12 weeks
17 weeks
17 weeks
17 weeks
Tumors"
M
16/19
(84%)b
16/20
(80%)b
18/20
(90%)b
4/17
(24%)b
15/16
(94%)b
18/18
(100%)b
F
—
—
—
—
—
—
Comments
Reference
VO
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
Urethane
(continued)
Species
(strain)
Mice
(Swiss)
Mice
(Swiss)
Target
site
liver
skin
Age
when
first
dosed
Control
Day 1
Day 1
Day 1
Day 1
Day 1
Day 1
Day5
Day 20
Day 40
Control
Day 1
Dose
route,
# doses
Control
s.c.
s.c.
s.c.
s.c.
s.c.
s.c.
s.c.
s.c.
s.c.
Control
s.c.
Dose
N/A
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
N/A
1 mg
urethane/g
body weight;
5% croton oil
Duration
of
exposure
N/A
lx
lx
lx
lx
lx
lx
lx
lx
lx
N/A
single
dose
urethane,
croton oil
applied
2x/week
for 10
mos
Age at
death
360-720
days
180 days
240 days
300 days
360 days
420 days
480 days
420 days
420 days
420 days
180-550
days
660 days
Tumor incidence11
M
10/227
(4.4%)
1/20
(5%)8
2/17
(12%)g
5/18
(28%)g
11/20
(55%)8
13/15
(87%)g
17/23
(74%)c
9/13
(69.2%)b
1/13
(8%)b
0/11
(0%)b
F
4/222
(8.22%)
0/20
(0%)c
0/12
(0%)c
0/16
(0%)c
0/23
(0%)c
2/22
(9%)8
2/25
(8%)c
2/11
(18.2%)b
0/16
(0%)b
0/9
(0%)b
30/712
(4.21%)
26/59
(44.1o/0)i
Comments
Croton oil treatment
initiated at 40 days of
age.
Reference
Chieco-Bianchi et
al. (1963)
Chieco-Bianchi et
al. (1963)
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
Urethane
(continued)
Species
(strain)
Mice
(B6AFi/J)
Mice
(B6AFi/J)
Target
site
liver
lung
Harderian
gland
Age
when
first
dosed
Day 40
Control
Day 1
Day?
Day 14
Day 21
Day 28
Control
Day 1
Day?
Day 14
Day 21
Day 28
Control
Day 1
Dose
route,
# doses
s.c.
gavage
gavage
gavage
Dose
1 mg
urethane/g
body weight;
5% croton oil
N/A
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
Duration
of
exposure
single
dose
urethane,
croton oil
applied
2x/week
for 10
mos
N/A
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
700 days
71 weeks
66 weeks
67 weeks
68 weeks
69 weeks
70 weeks
71 weeks
66 weeks
67 weeks
68 weeks
69 weeks
70 weeks
71 weeks
66 weeks
Tumor incidence11
M
F
8/41
(19.5%)b
1/25
(4%)
9/20
(45%)8
20/22
(91%)8
16/20
(80%)g
13/23
(57%)8
4/24
(17%)8
9/25
(36%)
20/20
(100%)b
22/22
(100%)b
19/20
(95%)b
23/23
(100%)b
24/24
(100%)b
0/25
(0%)
0/20
(0%)c
0/25
(0%)
9/26
(35%)g
20/26
(77%)8
10/23
(43%)s
1/20
(5%)s
1/20
(5%f
6/25
(24%)
25/26
(96%)b
26/26
(100%)b
19/23
(83%)b
19/20
(95%)b
20/20
(100%)b
0/25
(0%)
1/26
(4%)b
Comments
Reference
Klein (1966)
Klein (1966)
>
-------
Table 3. Methodological information and tumor incidence for animal studies with early postnatal and juvenile
and adult acute exposure (continued)
Chemical
Urethane (continued)
Species
(strain)
Target
site
forestomach
Age
when
first
dosed
Day?
Day 14
Day 21
Day 28
Control
Day 1
Day?
Day 14
Day 21
Day 28
Dose
route,
# doses
gavage
Dose
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
1 mg/g body
weight
Duration
of
exposure
lx
lx
lx
lx
lx
lx
lx
lx
lx
lx
Age at
death
67 weeks
68 weeks
69 weeks
70 weeks
71 weeks
66 weeks
67 weeks
68 weeks
69 weeks
70 weeks
Tumor incidence11
M
0/22
(0%)c
0/20
(0%)c
1/23
(4%)b
0/24
(0%)c
0/25
(0%)
0/20
(0%)c
1/22
(5%)b
1/20
(5%)b
0/23
(0%)c
2/24
(8%)b
F
1/26
(4%)b
2/23
(9%)b
0/20
(0%)c
0/20
(0%)c
1/25
(4%)
3/26
(12%)b
1/26
(4%)b
4/23
(17%)b
1/20
(5%)b
1/20
(5%)b
Comments
Reference
to
a Where not delineated by gender, data combined by study authors or gender not specified. Where percentages only are given, number of subjects not specified.
bNot evaluated by authors.
0 Evaluated but not significant compared with controls.
d Study also included mammary fibroadenomas and fibromas as well as other types of cancers.
e 8-9 weeks old.
f Includes survivors up to 40 weeks only.
8 Significant compared with controls.
i.p. = intraperitoneal injection; s.c. = subcutaneous injection
-------
Table 4. Ratio of early-life to adult cancer potencies for studies with repeated exposures of juvenile and adult
animals to carcinogens with a mutagenic mode of action*
Compound
Benzidine
3-MU
3-Methylcholanthrene
(formerly known as 20-
methylcholanthrene)
Safrole
VC
Vinyl chloride
Species
(strain)
Mice (B6C3FO
Mice (Albino)
Mice (B6C3FO
Rats (Sprague-
Dawley)
Sex
male
female
male
female
male
female
male
female
male
female
male
male
female
female
male
male
female
female
male
female
female
male
male
female
female
male
male
Dose
0.25 mg/g
0.25 mg/g
0.25 mg/g
0.25 mg/g
0.25 mg/g
0.25 mg/g
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
Tumor
liver
liver
hepatoma
hepatoma
forestomach
forestomach
skin
skin
liver
liver
liver-angiosarcoma
liver-angiosarcoma
liver-angiosarcoma
liver-angiosarcoma
zymbal gland
zymbal gland
zymbal gland
zymbal gland
leukemia
leukemia
leukemia
nephroblastomas
nephroblastomas
nephroblastomas
nephroblastomas
angiosarcomas-
other sites
angiosarcomas-
Unweighted
geometric
mean
111
0.16
33
7.7
0.91
1.5
1.8
1.5
47
0.12
6.7
7.4
13
30
0.73
0.27
0.48
0.15
21
1.3
0.29
0.15
0.17
0.28
0.24
0.9
0.25
2.5%
64
0.004
7.4
1.1
0.39
0.58
0.048
0.023
16
0.002
0.035
0.035
4.9
8.7
0.0032
0.0022
0.0027
0.0014
0.026
0.0035
0.0019
0.0014
0.0015
0.0018
0.0017
0.0033
0.0017
Median
110
0.22
30
7.1
0.91
1.5
2.1
1.8
44
0.18
9.8
11
13
29
1.1
0.4
0.7
0.19
37
1.7
0.35
0.19
0.21
0.33
0.29
1.26
0.30
97.5%
198
1.1
268
85
2.1
4.2
22
21
198
1.1
57
62
33
121
30
5.4
16
4.5
514
153
17
4.8
6.2
16
11
53
12
Reference
Vesselinovitch et al.
(1975b)
Klein (1959)
Vesselinovitch et al.
(1979b)
Maltonietal. (1984)
-------
Table 4. Ratio of early-life to adult cancer potencies for studies with repeated exposures of juvenile and adult
animals to mutagenic chemicals (continued)
Compound
VC
Vinyl chloride
(continued)
Species
(strain)
Sex
female
female
male
male
female
female
male
male
female
female
male
male
female
female
male
male
female
female
Dose
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
6,000 ppm
10,000 ppm
Tumor
other sites
angiosarcomas-
other sites
angiosarcomas-
other sites
angiomas &
fibromas-other
sites
angiomas &
fibromas-other
sites
angiomas &
fibromas-other
sites
angiomas &
fibromas-other
sites
hepatoma
hepatoma
hepatoma
hepatoma
skin carcinomas
skin carcinomas
skin carcinomas
skin carcinomas
neuroblastoma
neuroblastoma
neuroblastoma
neuroblastoma
Unweighted
geometric
mean
0.24
0.32
0.72
1.4
0.27
0.52
62
34
55
55
1.1
0.41
0.46
0.31
0.21
0.20
0.27
0.14
2.5%
0.0017
0.0019
0.0031
0.0045
0.0018
0.0024
11
8.2
13
8.4
0.0035
0.0024
0.0024
0.0019
0.0016
0.0016
0.0018
0.0014
Median
0.29
0.38
1.0
2.36
0.33
0.63
58
32
51
53
1.5
0.56
0.59
0.37
0.26
0.24
0.32
0.18
97.5%
11
20
33
47
16
41
543
218
352
513
82
15
24
19
9.5
8.5
15
4.4
Reference
The 2.5% and 97.5% are percentiles of the posterior distribution. For a Bayesian distribution, these percentiles function in a
manner similar to the 95% confidence limits for other types of statistical analyses.
-------
Table 5. Ratio of early-life to adult cancer potencies for studies with repeated exposures of juvenile and adult animals
to chemicals with a nonmutagenic mode of action*
Compound
Amitrole
DDT
Dieldrin
DPH
ETU
PBB
Species
(strain)
Mice (B6C3FO
Mice (B6C3FO
Mice (B6C3FO
Rats (F344/N)
Mice (B6C3FO
Rats (F344/N)
Mice (B6C3FO
Rats (F344/N)
Mice (B6C3FO
Sex
male
female
male
male
male
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
Dose
NA
NA
NA
NA
630
630
210
210
90
90
330
330
330
330
330
330
10
10
10
10
30
30
Tumor
liver
liver
liver
liver
liver
liver
liver
liver
thyroid
thyroid
liver
liver
thyroid
thyroid
pituitary
pituitary
liver
liver
mononuclear
cell leukemia
mononuclear
cell leukemia
liver
liver
Ratio of juvenile to adult potency
Unweighted
geometric
mean
13
0.14
1.3
0.75
0.4
0.24
1.5
1.3
0.37
0.23
0.091
0.057
0.41
0.4
0.32
0.24
0.59
0.063
0.79
0.21
3.9
1.0
2.5%
5.1
0.0013
0.0044
0.0031
0.0024
0.0017
0.0040
0.0056
0.0029
0.0018
0.0011
0.0010
0.0022
0.0024
0.0019
0.0018
0.0041
0.0009
0.0035
0.0017
1.9
0.37
Median
14
0.18
2.5
1.2
0.54
0.29
2.4
2.6
0.61
0.3
0.12
0.081
0.52
0.55
0.38
0.32
1.1
0.079
1.4
0.28
3.9
1.05
97.5%
30
3.9
25
27
16
12
71
15
5.4
7.0
1.9
0.65
25
16
22
6.9
6.6
1.2
18
6.0
7.5
2.1
Reference
Vesselinovitch(1983)
Vesselinovitch et al.
(1979a)
Vesselinovitch et al.
(1979a)
Chhabraetal. (1993b)
Chhabraetal. (1992)
Chhabraetal. (1993a)
The 2.5% and 97.5% are percentiles of the posterior distribution. For a Bayesian distribution, these percentiles function in a
manner similar to the 95% confidence limits for other types of statistical analyses.
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult animals to
carcinogens with a mutagenic mode of action*
Compound
BaP*
Species
(strain)
Mice (B6C3FO
Mice (C3AFO
Mice (B6C3FO
Mice (C3AFO
Sex
male
female
male
female
male
female
male
female
Male
female
Male
female
male
Dose
75 ng/kg
75 ng/kg
150 ng/kg
150 ng/kg
75 ng/kg
75 ng/kg
150 ng/kg
150 ng/kg
75 ng/kg
75 ng/kg
150 ng/kg
150 ng/kg
75 ng/kg
Tumor
liver
liver
lung
lung
lung
lung
lung
Day
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Ratio of juvenile to adult potency
Unweighted
geometric
mean
9.3
11
1.2
1.7
29
15
8.8
1.2
11
7.5
0.2
0.2
14
3.6
0.2
0.2
1.2
0.2
2.8
1.4
2.2
0.8
7.9
3.7
1.2
1.1
2.5%
2.9
3.5
0.0083
0.015
8.2
4.1
1.4
0.0082
2.1
1.1
0.0018
0.0017
3.0
0.11
0.0017
0.0017
0.45
0.0046
1.096
0.41
1.0
0.2
2.6
1.1
0.47
0.43
Median
8.4
9.6
1.6
2.1
26
13
8.1
1.6
10
7.0
0.26
0.24
12.8
3.8
0.24
0.24
1.2
0.31
2.7
1.4
2.1
0.82
7.2
3.4
1.2
1.08
97.5
%
55
61
31
36
194
109
94
30
112
83
9.1
8.5
130
49
8.8
8.7
3.4
1.4
9.5
5.1
5.4
2.3
43
22
3.2
3.1
Reference
Vesselinovitch et al.
(1975a)
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
BaP*
(continued)
DBA
DEN**
Species
(strain)
Mice
Mice (B6C3FO
Mice (C3AFO
Mice (B6C3FO
Sex
female
male
female
male
female
male
female
male
female
male
female
male
female
Dose
75 ng/kg
150 ng/kg
150 ng/kg
6 ng/kg
6 ng/kg
12 ng/kg
12 ng/kg
6 ng/kg
6 ng/kg
12 ng/kg
12 ng/kg
6 ng/kg
6 ng/kg
Tumor
lung
lung
lung
lung
liver
liver
liver
liver
liver
liver
liver
liver
lung
lung
Day
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Ratio of juvenile to adult potency
Unweighted
geometric
mean
1.6
1.6
1.5
1.9
1.3
1.2
178
9.0
8.9
35
25
9.6
9.8
16
19
7.3
3.5
17
6.4
11
9.8
40
25
0.5
1.6
0.9
1.2
2.5%
0.66
0.71
0.57
0.71
0.61
0.54
20
3.5
3.5
9.1
6.3
3.3
3.4
5.9
7.1
2.9
1.4
3.2
0.86
3.7
3.4
8.5
5.0
0.27
0.95
0.54
0.76
Median
1.55
1.63
1.5
1.8
1.3
1.1
143
8.3
8.2
31
226
8.8
8.9
15
18
6.9
3.3
16
6.0
9.5
8.9
36
22
0.52
1.6
0.89
1.2
97.5
%
4.0
4.2
5.0
6.0
2.9
2.6
5100
37
36
239
175
50
51
67
79
26
13
166
73
53
50
340
221
0.93
2.7
1.5
2.0
Reference
Law (1940)
Vesselinovitch et al.
(1984)
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
DEN**
(continued)
DMBA*
Species
(strain)
Mice (C3AFO
Rats (Wistar)
Mice (Balb/c)
Mice (Swiss)
Sex
male
female
male
female
male
female
male
female
male
male
female
female
Dose
12 ng/kg
12 ng/kg
6 ng/kg
6 ng/kg
12 ng/kg
12 ng/kg
15 Hg
30 ngx2
15 Hg
30|igx2
Tumor
lung
lung
lung
lung
lung
lung
total
total
mammary
lung
lung
lung
lung
lymphoma
lung
Day
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
Iday
15 days
2 vs 5-8 wks
2 vs 26 wks
2 vs 5-8 wks
2 vs 26 wks
2 vs 5-8 wks
2 vs 26 wks
5 vs 26 wks
Iday
15-1 9 days
15-1 9 days
Iday
15-1 9 days
15-1 9 days
Ratio of juvenile to adult potency
Unweighted
geometric
mean
0.4
0.7
0.7
1.4
0.7
0.5
1.1
0.7
0.3
0.6
0.7
0.7
3.3
3.2
1.3
3.3
0.0
0.2
7.1
30
1.0
14
60
3.1
15
2.7
9.1
2.5%
0.21
0.39
0.44
0.88
0.22
0.21
0.45
0.36
0.084
0.26
0.35
0.37
1.3
1.3
0.68
1.2
0.0012
0.0023
1.8
2.8
0.28
1.056
6.0
0.51
1.2
0.60
2.9
Median
0.40
0.66
0.73
1.4
0.67
0.56
1.1
0.74
0.33
0.62
0.75
0.75
3.2
3.1
1.3
3.0
0.056
0.29
6.4
22
1.0
10
46
3.0
11
2.5
8.7
97.5
%
0.73
1.1
1.2
2.3
1.7
1.3
2.5
1.5
0.76
1.4
1.6
1.5
10
9.7
2.5
16
0.26
5.3
55
1482
3.5
978
2350
22
1004
19
40
Reference
Meranzeetal. (1969)
Walters (1966)
Pietraetal. (1961)
oo
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
DMN***
ENU
Species
(strain)
Rats (Wistar)
Mice (B6C3FO
Rats (Wistar)
Mice (B6C3FO
Sex
male
female
male
female
male
female
male
Dose
3 wks
24 hr
1 month
60 |ig/g
60 ng/g
120 ng/g
Tumor
total
liver
nerve tissue
lung
lung
lung
Day
1 month
1.5 months
2 months
3 months
1 month
1.5 months
2 months
3 months
1.5 months
2 months
3 months
1 day
1 week
2 weeks
3 weeks
Iday
1 weeks
2 weeks
3 weeks
1
15
1
15
1
Ratio of juvenile to adult potency
Unweighted
geometric
mean
0.7
1.1
1.5
0.9
0.3
0.4
0.6
0.4
1.5
2.0
1.3
7.8
7.1
27
1.6
1.6
0.7
64
9.6
6.2
0.7
1.0
1.1
2.1
1.0
1.0
2.5%
0.41
0.58
0.75
0.50
0.13
0.18
0.24
0.16
0.80
1.0
0.69
3.9
2.9
2.5
0.61
0.58
0.12
6.0
2.6
1.6
0.0090
0.60
0.66
1.17
0.60
0.60
Median
0.73
1.1
1.5
0.94
0.28
0.42
0.56
0.36
1.52
2.0
1.3
7.7
6.9
20
1.6
1.6
0.72
50
8.9
5.7
0.89
1.0
1.1
2.1
1.0
1.0
97.5
%
1.3
2.1
3.0
1.8
0.6
0.9
1.3
0.78
3.0
4.2
2.5
18
21
1374
4.6
4.8
2.3
2488
59
40
8.9
1.7
1.8
4.1
1.7
1.7
Reference
Hard (1979)
Vesselinovitch(1983)
Naitoetal. (1981)
Vesselinovitch et al.
(1974)
VO
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
ENU
(continued)
Species
(strain)
Mice (C3AFO
Mice (B6C3FO
Mice (C3AFO
Mice (B6C3FO
Sex
female
male
female
male
female
male
female
male
female
male
female
male
female
male
Dose
120 ng/g
60 ng/g
60 ng/g
120 ng/g
120 ng/g
60 ng/g
60 ng/g
120 ng/g
120 ng/g
60 ng/g
60 |ig/g
120 ng/g
120 ng/g
60 ng/g
Tumor
lung
lung
lung
lung
lung
liver
liver
liver
liver
liver
liver
liver
liver
kidney
Day
15
1
15
1
15
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
Ratio of juvenile to adult potency
Unweighted
geometric
mean
1.1
2.1
1.0
8.7
52
0.7
0.9
0.7
0.5
0.4
8.8
14
6.3
5.6
5.2
7.6
11
14
12
8.1
7.5
4.8
9.8
6.6
5.4
5.4
2.2
1.2
2.5%
0.66
1.2
0.60
2.7
5.2
0.32
0.38
0.28
0.24
0.18
4.2
6.2
2.6
2.4
2.5
3.9
4.1
4.9
4.7
3.2
2.6
1.8
4.1
2.7
1.7
1.7
0.73
0.29
Median
1.0
2.1
1.0
8.0
39
0.72
0.92
0.67
0.54
0.42
8.5
14
6.1
5.4
5.1
7.5
11
13
11
7.6
7.0
4.6
9.3
6.3
5.0
5.1
2.1
1.2
97.5
%
1.8
4.1
1.7
48
2141
1.6
2.2
1.6
1.2
0.92
22
37
18
16
11
17
46
55
43
29
32
18
32
23
25
25
8.0
5.1
Reference
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
ENU
(continued)
Species
(strain)
Mice (C3AFO
Mice (B6C3FO
Mice (C3AFO
Sex
female
male
female
male
female
male
female
male
female
male
female
male
female
male
Dose
60 ng/g
120 ng/g
120 ng/g
60 ng/g
60 ng/g
120 ng/g
120 ng/g
60 ng/g
60 |ig/g
120 ng/g
120 ng/g
60 ng/g
60 ng/g
120 ng/g
Tumor
kidney
kidney
kidney
kidney
kidney
kidney
kidney
Harderian
Harderian
Harderian
Harderian
Harderian
Harderian
Harderian
Day
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
Ratio of juvenile to adult potency
Unweighted
geometric
mean
0.7
2.6
1.7
2.6
0.9
1.4
1.8
2.0
1.0
2.1
0.2
1.5
2.3
7.1
0.3
0.5
0.1
0.8
0.4
0.6
0.1
0.7
0.1
0.1
0.4
0.8
0.1
0.3
2.5%
0.024
0.61
0.65
1.14
0.37
0.67
0.17
0.25
0.016
0.16
0.0029
0.38
0.17
1.8
0.018
0.075
0.0025
0.35
0.13
0.26
0.0030
0.17
0.0023
0.0016
0.019
0.15
0.0010
0.0050
Median
0.85
2.5
1.7
2.6
0.87
1.4
1.9
2.0
1.3
2.2
0.24
1.5
2.4
6.5
0.41
0.52
0.16
0.84
0.42
0.57
0.18
0.77
0.20
0.18
0.52
0.85
0.086
0.40
97.5
%
5.9
15
4.4
6.4
2.0
3.2
15
16
13
20
1.5
5.9
20
47
1.4
1.4
0.74
2.0
0.96
1.2
0.85
2.1
1.3
1.8
2.5
3.4
1.0
2.8
Reference
>
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
ENU
(continued)
NMU
Species
(strain)
Mice (B6C3FO
Mice (C3AFO
Mice (BC3FO
Sex
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
Dose
120 ng/g
60 ng/g
60 ng/g
120 ng/g
120 ng/g
60 ng/g
60 ng/g
120 ng/g
120 ng/g
50 jjg/g
50 jjg/g
50 ng/g
50 |ig/g
50 |ig/g
50 |ig/g
50 |ig/g
50 |ig/g
50 ng/g
50 ng/g
Tumor
Harderian
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
lung adenomas
lung adenomas
lymphosarcoma
lymphosarcoma
hepatoma
hepatoma
renal adenoma
renal adenoma
forestomach
forestomach
Day
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
15
1
1
1
1
1
1
1
1
1
1
Ratio of juvenile to adult potency
Unweighted
geometric
mean
0.1
0.1
0.3
1.9
0.2
0.2
0.2
1.2
0.6
1.6
0.0
0.3
0.8
1.1
0.2
0.7
0.4
0.6
3.4
6.3
2.5
1.1
35
0.3
0.9
1.3
0.0
0.1
2.5%
0.0012
0.0012
0.0091
0.61
0.0083
0.0072
0.0059
0.50
0.19
0.67
0.0009
0.023
0.085
0.19
0.010
0.32
0.14
0.24
1.3
2.4
1.1
0.49
6.5
0.0023
0.0093
0.0081
0.0006
0.0027
Median
0.094
0.081
0.34
1.82
0.26
0.24
0.20
1.2
0.60
1.6
0.063
0.41
0.89
1.1
0.19
0.70
0.46
0.64
3.3
6.0
2.4
1.1
32
0.39
1.2
1.7
0.039
0.15
97.5
%
1.2
0.90
2.4
8.7
1.1
1.0
0.90
2.9
1.5
3.7
0.51
1.3
3.5
4.5
0.56
1.5
1.2
1.5
9.3
23
6.4
2.4
324
13
13
33
0.52
0.69
Reference
Terracini and Testa
(1970)
to
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
NMU
(continued)
Species
(strain)
Mice (C3Hf/Dp)
Sex
male
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
Dose
25 Hg/g
25 Hg/g
25 ng/g
25 ng/g
25 ng/g
25 |ig/g
25 |ig/g
25 |ig/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
50 ng/g
Tumor
thymic
lymphoma
thymic
lymphoma
lung adenomas
lung adenomas
liver tumor
liver tumor
Stomach
Stomach
ovarian
uterine/vaginal
thymic
lymphoma
thymic
lymphoma
lung adenomas
lung adenomas
liver tumor
liver tumor
Stomach
Stomach
ovarian
uterine/vaginal
thymic
lymphoma
thymic
lymphoma
lung adenomas
lung adenomas
Day
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
21
21
21
21
Ratio of juvenile to adult potency
Unweighted
geometric
mean
1.9
1.2
1.0
0.4
0.2
0.3
0.5
0.3
0.1
8.6
7.9
3.1
0.04
0.1
0.2
0.1
0.01
0.1
0.0
0.0
4.3
1.0
0.1
0.7
2.5%
0.048
0.0089
0.013
0.018
0.0016
0.0026
0.0045
0.0046
0.0014
1.1
3.1
1.3
0.0008
0.0012
0.0021
0.0011
0.0003
0.0022
0.0003
0.0005
1.6
0.39
0.0022
0.30
Median
2.1
1.5
1.2
0.46
0.21
0.39
0.67
0.43
0.17
8.1
7.4
3.0
0.058
0.084
0.33
0.13
0.013
0.15
0.014
0.034
4.1
1.0
0.22
0.75
97.5
%
23
30
11
1.7
4.6
4.4
6.8
3.8
3.5
97
30
7.8
0.45
0.53
7.8
4.5
0.12
0.96
0.14
0.46
17
2.6
1.1
1.7
Reference
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
NMU
(continued)
Urethane
Urethane +
croton oil
Urethane
Species
(strain)
Mice (Swiss)
Mice (Swiss)
Rats (MRC
Wistar-derived)
Mice (Swiss)
Mice (Swiss)
Sex
male
female
male
female
male
female
male
female
male
female
both
both
male/
female
male/
female
male/
female
male/
female
male/
female
male/
female
male/
female
Dose
50 ng/g
50 ng/g
50 ng/g
50 ng/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
16%x6
16%x6
16%x6
16%x6
16%x6
16%x6
1 mg/g
Tumor
liver tumor
liver tumor
stomach
stomach
ovarian
uterine/vaginal
liver
liver
liver
liver
liver
liver
skin
skin
neurilemmomas
neurilemmomas
liver
liver
thyroid
thyroid
lung
leukemia
Day
21
21
21
21
21
21
1
1
5
5
20
20
1
1
1
28
1
28
1
28
1
Ratio of juvenile to adult potency
Unweighted
geometric
mean
0.1
0.9
0.1
1.8
0.0
1.7
24
0.4
14
1.2
0.2
0.1
0.2
2.9
0.2
0.4
7.9
0.2
0.0
0.1
15
6.7
2.5%
0.0013
0.0051
0.001
0.77
0.0007
0.59
4.4
0.0044
2.4
0.017
0.0018
0.0011
0.0027
1.2
0.0028
0.0045
1.4
0.0026
0.0006
0.0011
1.2
1.7
Median
0.15
1.4
0.08
1.8
0.055
1.7
21
0.54
13
1.4
0.28
0.12
0.32
2.8
0.33
0.51
7.1
0.4
0.039
0.1
11
6.1
97.5
%
4.3
23
0.64
4.7
0.97
6.4
220
13
137
26
10
4.8
5.4
8.2
4.5
6.3
82
11.7
0.67
1.5
997
45
Reference
Chieco-Bianchi et al.
(1963)
Choudari Kommineni et
al. (1970)
De Benedictis et al.
(1962)
Fiore-Donati et al.
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
Urethane
(continued)
Species
(strain)
Mice (B6AFJ/J)
Mice (C3H/f)
Mice (Swiss)
Sex
male
female
male
male
female
male
female
male
female
male
female
male
female
male
female
male
female
male
female
Dose
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
1 mg/g
Tumor
liver
liver
Harderian gland
Harderian gland
forestomach
forestomach
forestomach
forestomach
forestomach
forestomach
forestomach
forestomach
lung
lung
lung
liver
liver
lung
lung
reticular tissue
reticular tissue
pulmonary
adenomas
Day
21
21
1
7
14
21
1
1
7
7
14
14
21
21
1
14
14
21
1
1
1
1
1
1
2 vs 4 weeks
Ratio of juvenile to adult potency
Unweighted
geometric
mean
5.1
5.1
0.2
0.3
0.3
0.6
0.3
0.1
0.4
0.1
0.1
0.2
0.8
0.1
0.2
1.0
0.8
0.4
0.9
14
16
5.9
22
2.0
8.6
14
2.5%
1.1
1.4
0.0019
0.0021
0.0021
0.0044
0.0024
0.0009
0.0028
0.0017
0.0013
0.0018
0.0056
0.0008
0.0015
0.36
0.26
0.16
0.31
4.0
3.2
1.7
4.5
0.023
2.3
1.1
Median
4.7
4.7
0.26
0.33
0.33
0.85
0.41
0.079
0.49
0.19
0.16
0.21
1.1
0.072
0.2
0.95
0.8
0.45
0.86
12
15
5.6
20
2.3
7.7
10.1
97.5
%
38
30
6.0
11
11
20
13
1.9
11
3.5
5.0
3.9
18
1.7
6.3
2.5
2.3
1.1
2.4
81
155
28
203
38
60
965
Reference
(1962)
Klein (1966)
Liebeltetal. (1964)
Rogers (1951)
-------
Table 6. Ratio of early-life to adult cancer potencies for studies with acute exposures of juveniles and adult
animals to carcinogens with a mutagenic mode of action (continued)
Compound
Urethane
(continued)
Species
(strain)
Sex
Dose
1 mg/g
1 mg/g
1 mg/g
0.25 mg/g
0.5 mg/g
1.0 mg/g
Tumor
pulmonary
adenomas
pulmonary
adenomas
pulmonary
adenomas
adenomas
adenomas
adenomas
Day
2 vs 6 weeks
2 vs 8 weeks
2 vs 10 weeks
3 vs 8 weeks
3 vs 8 weeks
3 vs 8 weeks
Ratio of juvenile to adult potency
Unweighted
geometric
mean
16
19
21
7.1
0.7
0.7
2.5%
1.3
1.6
1.9
2.3
0.29
0.28
Median
11.3
13.3
14.5
6.7
0.67
0.68
97.5
%
1025
1126
1168
29
1.6
1.6
Reference
The 2.5% and 97.5% are percentiles of the posterior distribution. For a Bayesian distribution, these percentiles function in a
manner similar to the 95% confidence limits for other types of statistical analyses.
-------
Table 7. Ratio of early-life to adult cancer potencies for studies with lifetime exposures starting with juvenile
and adult animals to carcinogens with mutagenic or nonmutagenic modes of action*
Compound
Species
(strain)
Sex
Dose
Tumor
Unweightedg
eometric
mean
2.5%
Median
97.5%
Reference
Mutagenic compounds
DEN
Safrole
Urethane
Rats (Colworth)
Mice (B6C3FO
Mice (B6AFJ/J)
male
female
male
female
multiple
2.5 mg/pup
2.5 mg/pup
liver
esophagus
liver
liver
liver
liver
2.8
0.18
50
4.0
79
0.47
0.0093
0.0015
3.7
0.007
0.36
0.0022
5.6
0.23
50
4.0
102
0.55
23
4.8
253
23
1,064
42
Petoetal. (1984)
Vesselinovitch et al.
(1979b)
Klein (1966)
Nonmutagenic compounds
DDT
Dieldrin
DPH
ETU
Mice (B6C3FO
Mice (B6C3FO
Rats (F344/N)
Mice (B6C3FO
Rats (F344/N)
male
female
male
female
male
female
630:800
630:2,400
630:800
630:2,400
210:100
210:300
210:200
210:600
90:83
90:250
90:83
90:250
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
thyroid
thyroid
thyroid
thyroid
23
91
0.31
0.36
0.33
0.33
0.71
14
0.32
0.35
0.23
9.1
0.37
0.61
0.0023
0.014
0.0019
0.0021
0.0019
0.0019
0.0028
0.03
0.002
0.0023
0.0017
1.1
0.0021
0.0034
0.58
14
0.37
0.45
0.39
0.39
0.93
23
0.42
0.53
0.3
10.5
0.46
1.1
23
91
18
17
21
21
49
214
13
8.8
7.3
27
19
10
Vesselinovitch et al.
(1979a)
Vesselinovitch et al.
(1979a)
Chhabraetal. (1993b)
Chhabraetal. (1992)
-------
Table 7. Ratio of early-life to adult cancer potencies for studies with lifetime exposures starting with juvenile
and adult animals to carcinogens with mutagenic or nonmutagenic modes of action (continued)
Compound
ETU
(continued)
PBB
Species
(strain)
Mice (B6C3FO
Rats (F344/N)
Mice (B6C3FO
Sex
male
female
male
female
male
female
male
female
male
male
female
female
male
female
male
Dose
330:330
330:1,000
330:330
330:1,000
330:330
330:1,000
330:330
330:1,000
330:330
330:1,000
330:330
330:1,000
10:10
10:30
10:10
10:30
10:10
10:30
10:10
10:30
30:30
30:30
10:10
Tumor
liver
liver
liver
liver
thyroid
thyroid
thyroid
thyroid
pituitary
pituitary
pituitary
pituitary
liver
liver
liver
liver
mononuclear cell
leukemia
mononuclear cell
leukemia
mononuclear cell
leukemia
mononuclear cell
leukemia
liver
liver
liver
Unweighted
geometric
mean
0.37
0.48
0.33
0.42
0.44
0.63
5.2
0.18
0.40
0.18
0.21
0.27
0.39
0.18
36
3.1
0.51
0.77
0.54
0.34
8.9
4.4
0.15
2.5%
0.0022
0.0027
0.0023
0.0025
0.0022
0.0035
0.011
0.0016
0.0021
0.0015
0.0016
0.0019
0.0023
0.0016
15
0.023
0.0025
0.0031
0.0026
0.0021
0.015
0.0075
0.0014
Median
0.5
0.75
0.5
0.65
0.52
1.12
10
0.24
0.47
0.22
0.26
0.36
0.56
0.25
36
4.6
0.69
1.1
0.74
0.45
12.2
6.2
0.2
97.5%
14
12
7.8
11
34
10
108
4.2
32
5.7
10
9.0
13
4.3
86
22
23
35
24
15
1,076
786
3.9
Reference
Chhabraetal. (1993a)
oo
-------
Table 7. Ratio of early-life to adult cancer potencies for studies with lifetime exposures starting with juvenile
and adult animals to carcinogens with mutagenic or nonmutagenic modes of action (continued)
Compound
Species
(strain)
Sex
female
Dose
10:10
Tumor
liver
Unweighted
geometric
mean
0.29
2.5%
0.0021
Median
0.43
97.5%
7.0
Reference
The 2.5% and 97.5% are percentiles of the posterior distribution. For a Bayesian distribution, these percentiles function in a
manner similar to the 95% confidence limits for other types of statistical analyses.
-------
Table 8. Summary of quantitative estimates of ratio of early-life to adult cancer potencies
Dose
Tissue
Number of
chemicals
Inverse-
weighted
geometric mean
ratio
Unweighted
Minimum
Unweighted
Maximum
Number of
ratios
Percentage >1
Chemicals with mutagenic mode of action
Repeated
Lifetime
Acute
Combined repeated and lifetime
Combined
Forestomach
Harderian
Kidney
Leukemia
Liver
Lung
Lymph
Mammary (wk 5 vs wk 26)
Mammary (wk 2 vs wk 5-8 or 26)
Nerve
Nerve (Day 1 comparison)
Ovarian
Reticular tissue
Thymic lymphoma
Thyroid
Uterine/vaginal
Day 1
Day 15
4
o
J
6
11
3
2
2
1
5
7
2
1
1
2
2
1
1
1
1
1
7
o
J
10.5
8.7
10.4
1.5
0.076
0.48
1.6
5.9
8.1
1.1
1.8
7.1
0.071
2.3
10
0.033
6.5
2.8
0.05
1.6
1.7
1.5
0.12
0.18
0.12
0.01
0.01
0.06
0.17
5.1
0.10
0.04
1.1
NA
NA
0.24
0.24
0.01
1.96
1.01
0.03
0.03
0.01
0.06
111
79
111
178
1.9
0.8
7.1
6.7
40
178
2.7
NA
NA
64
64
0.13
8.6
7.9
0.08
8.6
178
52
45
6
51
268
32
20
18
2
70
77
3
1
2
8
3
3
2
6
2
o
J
127
74
42
67
45
55
16
0.0
78
100
77
56
100
100
0
75
67
0
100
100
0
67
55
65
Chemicals with nonmutagenic mode of action
Repeated
Lifetime
6
5
2.2
3.4
0.06
0.15
13
36
22
38
27
21
-------
Table 9. Excess Relative Risk (ERR) estimates for cancer incidence from
Life Span Study (Japanese survivors)3
Site
Stomach
Colon
Liver
Lung
Bone and connective tissue
Skin
Breast
Urinary bladder
Leukemia
Average ERR at 1 Sv
<20b
0.74
0.62
1.3
0.57
11
5.4
3.3
0.71
6.1
>20b
0.24
0.7
0.31
1.1
0.42
0.39
0.98
0.79
3.7
1 Information extracted from tables in UNSCEAR, Annex I (2000).
3 Age at exposure.
A-61
-------
Table 10. Excess Relative Risk (ERR) estimates for incidence of thyroid
cancer from Life Span Study3
Age at exposure
0-9 yr
10-19 yr
20-29 yr
>30yr
Average ERR at 1
(No. cases)
Sv
10.25 (24)
4.5 (35)
0.10 (18)
0.04 (55)
"Information extracted from tables in UNSCEAR, Annex I (2000).
A-62
-------
Table 11. Coefficients for the Revised Methodology mortality risk model
(from U.S. EPA, 1999)a
Cancer type
Risk model
type"
Age group
0-9
10-19
20-29
30-39
40+
Male:
Stomach
Colon
Liver
Lung
Bone
Skin
Breast
Ovary
Bladder
Kidney
Thyroid
Leukemia
R
R
R
R
A
A
R
R
R
R
A
R
1.223
2.290
0.9877
0.4480
0.09387
0.06597
0.0
0.0
1.037
0.2938
0.1667
982.3
1.972
2.290
0.9877
0.4480
0.09387
0.06597
0.0
0.0
1.037
0.2938
0.1667
311.3
2.044
0.2787
0.9877
0.0435
0.09387
0.06597
0.0
0.0
1.037
0.2938
0.1667
416.6
0.3024
0.4395
0.9877
0.1315
0.09387
0.06597
0.0
0.0
1.037
0.2938
0.1667
264.4
0.2745
0.08881
0.9877
0.1680
0.09387
0.06597
0.0
0.0
1.037
0.2938
0.1667
143.6
Female:
Stomach
Colon
Liver
Lung
Bone
Skin
Breast
Ovary
Bladder
Kidney
Thyroid
Leukemia
R
R
R
R
A
A
R
R
R
R
A
R
3.581
3.265
0.9877
1.359
0.09387
0.06597
0.7000
0.7185
1.049
0.2938
0.3333
1,176
4.585
3.265
0.9877
1.359
0.09387
0.06597
0.7000
0.7185
1.049
0.2938
0.3333
284.9
4.552
0.6183
0.9877
0.1620
0.09387
0.06597
0.3000
0.7185
1.049
0.2938
0.1667
370.06
0.6309
0.8921
0.9877
0.4396
0.09387
0.06597
0.3000
0.7185
1.049
0.2938
0.1667
178.8
0.5424
0.1921
0.9877
0.6047
0.09387
0.06597
0.1000
0.7185
1.049
0.2938
0.1667
157.1
a The coefficients were derived using several models applied to data from A-bomb survivors and selected medical
exposures.
b A = absolute risk with coefficient units of 10"4 (Gy y)"1; R= relative risk with coefficient units of Gy"1.
A-63
-------
REFERENCES
Anderson, LM; Diwan, BA; Fear, NT; et al. (2000) Critical windows of exposure for children's health: cancer in human
epidemiological studies and neoplasms in experimental animal models. Environ Health Perspect 108(Suppl 3):573-594.
Barton, HA; Cogliano, VJ; Flowers, L; Valcovic, L; Setzer, RW; Woodruff, TJ. (2005). Assessing susceptibility from early-
life exposure to carcinogens. Environ Health Perspect (in press).
Birch, JM; Blair, V; Kelsey, AM; et al. (1998) Cancer phenotype correlates with constitutional TP53 genotype in families
with the Li-Fraumeni syndrome. Oncogene 17:1061-1068.
Birnbaum, LS; Fenton, SE. (2003) Cancer and developmental exposure to endocrine disrupters. Environ Health Perspect
111:389-394.
Bosland, MC. (1996) Hormonal factors in carcinogenesis of the prostate and testis in humans and in animal models. Prog
ClinBiol Res 394:309-352.
Carlin, BP; Louis, TA. (2000). Bayes and empirical Bayes methods for data analysis: 2nd ed. Boca Raton, Fl: Chapman and
Hall/CRC.
Carthew, P; Rich, KJ; Martin, EA; et al. (1995) DNA damage as assessed by 32P-postlabelling in three rat strains exposed to
dietary tamoxifen: the relationship between cell proliferation and liver tumor formation. Carcinogenesis 16:1299-1304.
Carthew, P; Edwards, RE; Nolan, BM; et al. (2000) Tamoxifen induces endometrial and vaginal cancer in rats in the absence
of endometrial hyperplasia. Carcinogenesis 21:793-797.
Carthew, P; Edwards, RE; Nolan, BM; et al. (1996) Tamoxifen associated uterine pathology in rodents: relevance to women.
Carcinogenesis 17:1577-1582.
Cattley, RC; Marsman, DS; Popp, JA. (1991) Age-related susceptibility to the carcinogenic effect of the peroxisome
proliferator WY-14,643 in rat liver. Carcinogenesis 12:469-473.
Chhabra, RS; Eustis, S; Haseman, JK; et al. (1992) Comparative carcinogenicity of the ethylene thiourea with or without
perinatal exposure in rats and mice. Fundam Appl Toxicol 18:405-417.
Chhabra, RS; Bucher, JR; Haseman, JK; et al. (1993a) Comparative carcinogenicity of polybrominated biphenyls with or
without perinatal exposure in rats and mice. Fundam Appl Toxicol 21:451-460.
Chhabra, RS; Bucher, JR; Haseman, JK; et al. (1993b) Comparative carcinogenicity of 5,5-diphenylhydantoin with or
without perinatal exposure in rats and mice. Fundam Appl Toxicol 21:174-186.
R- 1
-------
Chieco-Bianchi, L; De Benedictis, G; Tridente, G; et al. (1963) Influence of age on susceptibility to liver carcinogenesis and
skin initiating action by urethane in Swiss mice. Br J Cancer 17:672-680.
Choudari Kommineni, VR; Greenblatt, M; Vesselinovitch, SD; et al. (1970) Urethan carcinogenesis in rats: importance of
age and dose. J Natl Cancer Inst 45(4):687-696.
Cimino, MC. (2001) New OECD genetic toxicology guidelines and interpretation of results. In: Choy, WN, ed. Genetic
toxicology and cancer risk assessment. New York, NY: Marcel Dekker, pp. 223-248.
Cohen, SM; Garland, EM; Cano, M; et al. (1995) Effects of sodium ascorbate, sodium saccharin and ammonium chloride on
the male rat urinary bladder. Carcinogenesis 16(11):2743-2750.
Cohen, SM; Anderson, TA; de Oliveira, LM; et al. (1998) Tumorogenicity of sodium ascorbate in male rats. Cancer Res
58:2557-2561.
Covelli, V; Di, MV; Bassani, B; et al. (1984) Influence of age on life shortening and tumor induction after x-ray and neutron
irradiation. RadiatRes 100:348-364.
Dearfield, KL; Auletta, AE; Cimino, MC; et al. (1991) Considerations in the U.S. Environmental Protection Agency's testing
approach for mutagenicity. Mutat Res 258:259-283.
Dearfield, KL; McCarroll, NE; Protzel, A; et al. (1999) A survey of EPA/OPP and open literature on selected pesticide
chemicals II. Mutagenicity and carcinogenicity of selected chloroacetanilides and related compounds. Mutat Res
443:183-221.
De Benedictis, G; Maiorano, G; Chieco-Bianchi, L., et al. (1962) Lung carcinogenesis by urethane in newborn, suckling, and
adult Swiss mice. Br J Cancer 16:686-689.
Delia Porta, G; Terracini, B. (1969) Chemical carcinogenesis in infant animals. Prog Exp Tumor Res 11:334-363.
Delongchamp, RR; Mabuchi, K; Yoshimoto,Y; et al. (1997) Cancer mortality among atomic bomb survivors exposed in utero
or as young children: October 1950-May 1992. RadiatRes 147:385-395.
Di, MV; Coppola, M; Rebessi, S; et al. (1990) Age-related susceptibility of mouse liver to induction of tumors by neutrons.
RadiatRes 124:227-234.
Diwan, BA; Kasprzak, KS; Rice, JM. (1992) Transplacental carcinogenic effects of nickel(II) acetate in the renal cortex,
renal pelvis and adenohypophysis in F344/NCr rats. Carcinogenesis 13(8): 1351-1357.
Diwan, BA; Riggs, CW; Logsdon, D; et al. (1999) Multiorgan transplacental and neonatal carcinogenicity of 3'azido-
deoxythymidine in mice. Toxicol Appl Pharmacol 161:82-99.
R- 2
-------
Drew, RT; Boorman, GA; Haseman, JK; et al. (1983) The effect of age and exposure duration on cancer induction by a
known carcinogen in rats, mice, and hamsters. Toxicol Appl Pharmacol 68:120-130.
Druckery, H. (1973) Chemical structure and action in transplacental carcinogenesis and teratogenesis. IARC Sci Pub
4:45-57.
Fenton, SE; Davis, CC. (2002) Atrazine exposure in utero increases dimethylbenz a anthracene-induced mammary tumor
incidence in long evans offspring. Toxicol Sci 66(1-2):185. "The Toxicologist, Abstracts of the 41st Annual Meeting of the
Society of Toxicology." (Abstract 903).
Fiore-Donati, L; De Benedictis, G; Chieco-Bianchi, L; et al. (1962) Leukaemogenic activity of Urethan in Swiss and AKR
mice. Nature 190:134-139.
Flammang, TJ; Von Tungeln, LS; Kadlubar, FF; et al. (1997) Neonatal mouse assay for tumorigenicity: alternative to the
chronic rodent bioassay. Regul Toxicol Pharmacol 26:230-240.
Fujii, K. (1991) Evaluations for the newborn mouse model for chemical tumorigenesis. Carcinogenesis 8:1409-1415.
Gass, GH; Coats, D; Graham, N. (1964) Carcinogenic dose-response curve to oral diethylstilbestrol. J Natl Cancer Inst
33:971-977.
Ginsberg, GL. (2003) Assessing cancer risks from short-term exposures in children. Risk Anal 23:19-34.
Ginsberg, G; Hattis, D; Sonawane, B; et al. (2002) Evaluation of child/adult pharmacokinetic differences from a database
derived from the therapeutic drug literature. Toxicol Sci 66:185-200.
Goddard, MJ; Krewski, D. (1995) The future of mechanistic research in risk assessment: where are we going and can we get
there from here? Toxicology 102:53-70.
Greenman, DL; Highman, B; Chen, J; et al. (1990) Estrogen-induced thyroid follicular cell adenomas in C57B1/6 mice. J
Toxicol Environ Health 29:269-278.
Grufferman, S. (1998) Methodologic approaches to studying environmental factors in childhood cancer. Environ Health
Perspect 106(Suppl 3):881-886.
Hale, GA; Marina, NM; Johnes-Wallace, D; et al. (1999) Late effects of treatment for germ cell tumors during childhood and
adolescence. J Pediatr Hematol Oncol 21:115-122.
Halmes, NC; Roberts, SM; Tolson, JK; et al. (2000) Reevaluating cancer risk estimates for short-term exposure scenarios.
Toxicol Sci 58:32-42.
R- 3
-------
Hard, GC. (1979) Effect of age at treatment on incidence and type of renal neoplasm induced in the rat by a single dose of
dimethylnitrosamine. Cancer Res 39:4965-4970.
Harris, D; Goble, R; and Chu, M. (2005) Age-related differences in susceptibility to carcinogenesis II. Approaches for
application and uncertainty analyses for individual genetically acting carcinogens. Environ Health Perspect 113:509-516..
Hatch, EE; Palmer, JR; Titus-Ernstoff, L; et al. (1998) Cancer risk in women exposed to diethylstilbestrol in utero. JAMA
280:630-634.
Hayashi, M; MacGregor, JT; Gatehouse, DG; et al. (2000) In vivo rodent erythrocyte micronucleus assay II. Some aspects of
protocol design including repeated treatments, integration with toxicity testing, and automated scoring. Environ Mol
Mutagen 35:234-252.
Holladay SD, Smialowicz RJ. 2000. Development of the murine and human immune system: differential effects of
immunotoxicants depend on time of exposure. Environ Health Perspect 108 Suppl 3:463-473.
Holsapple MP, West LJ, Landreth KS. 2003. Species comparison of anatomical and functional immune system development.
Birth Defects Res B Dev Reprod Toxicol 68(4):321-334.
Israel, MA. (1995) Molecular biology of childhood neoplasms. In: Mendelsohn, J; Howley, PM; Israel, MA; et al.; eds. The
molecular basis of cancer. Saunders; Philadelphia, PA: pp. 294-316.
Jurgelski, Jr, W; Hudson, P; Falk, HL. (1979) Tissue differentiation and susceptibility to embryonal tumor induction by
ethylnitrosourea in the opossum. NCI Monograph 51: 123-158.
Kaye, AM; Trainin, N. (1966) Urethan carcinogenesis and nucleic acid metabolism: Factors influencing lung adenoma
induction. Cancer Res 26:2206-2212.
Klein, M. (1959) Development of hepatomas in inbred albino mice following treatment with 20-Methylcholanthrene. Cancer
Res 19:1109-1113.
Klein, M. (1966) Influence of age on induction with urethan of hepatomas and other tumors in infant mice. J Natl Cancer
Inst 36(6): 111 1-1120.
Kraupp-Grasl, B; Huber, W; Taper, H; et al. (1991) Increased susceptibility of aged rats to hepatocarcinogenesis by the
peroxisome proliferator nafenopin and the possible involvement of altered liver foci occurring spontaneously. Cancer Res
51:666-671.
Kushner, BH; Heller, G; Cheung, NK; et al. (1998) High risk of leukemia after short-term dose-intensive chemotherapy in
young patients with solid tumors. J Clin Oncol 16:3016-3020.
Laib, RJ; Bolt, HM; Cartier, R; et al. (1989) Increased alkylation of liver DNA and cell turnover in young versus old rats
exposed to vinyl chloride correlates with cancer susceptibility. Toxicol Lett 45:231-239.
R- 4
-------
Larson, RA; LeBeau, MM; Vardiman, JW; et al. (1996) Myeloid leukemia after hematotoxins. Environ Health Perspect
104(Suppl 6): 1303-1307.
Laurenzana, EM; Weis, CC; Bryant, CW; et al. (2002) Effect of dietary administration of genistein, nonylphenol or ethinyl
estradiol on hepatic testosterone metabolism, cytochrome P-450 enzymes, and estrogen receptor alpha expression. Food
Chem Toxicol 40:53-63.
Law, LW. (1940) The production of tumors by injection of a carcinogen into the amniotic fluid of mice. Science 91:96-97.
Liebelt, RA; Leibelt, AG; Lane, M. (1964) Hormonal influences on urethan carcinogenesis in C3H/f mice. Cancer Res
24:1869-1879.
Lindahl, T; Klein, G; Reedman, BM; et al. (1974) Relationship between Epstein-Barr virus (EBV) DNA and the EBV-
determined nuclear antigen (EBNA) in Burkitt lymphoma biopsies and other lymphoproliferative malignancies. Int J Cancer
13:764-772.
Maekawa, A; Mitsumori, K. (1990) Spontaneous occurrence and chemical induction of neurogenic tumors in rats-influence
of host factors and specificity of chemical structure. Crit Rev Toxicol 20(4):287-310.
Mahoney, FJ. (1999) Update on diagnosis, management, and prevention of hepatitis B virus infection. Clin Microbiol Rev
12:351-366.
Maltoni, C; Lefemine, G; Ciliberti, A; et al. (1981) Carcinogenicity bioassays of vinyl chloride monomer: a model of risk
assessment on an experimental basis. Environ Health Perspect 41:3-29.
Maltoni, C; Lefemine, G; Ciliberti, A; et al. (1984) Experimental research on vinyl chloride carcinogenesis. In: Maltoni, C;
Mehlaman, MA; eds. Archives of Research on Industrial Carcinogenesis. Vol. II. Princeton, NJ: Princeton Scientific
Publishing.
McCarroll, NE; Protzel, A; loannou, Y; et al. (2002) A survey of EPA/OPP and open literature on selected pesticide
chemicals. III. Mutagenicity and carcinogenicity of benomyl and carbendazim. Mutat Res 512:1-35.
McClain, R; Keller, D; Casciano, D; et al. (2001) Neonatal mouse model: review of methods and results. Toxicol Pathol
29(Suppl): 128-137.
McConnell, EE. (1992) Comparative response in carcinogenesis bioassay as a function of age at first exposure. In: Guzelian,
P; Henry, CJ; Olin, SS; eds. Similarities and difference between children and adults: implications for risk assessment.
Washington, DC: ILSI Press; pp. 66-78.
McCurdy, T; Glen, G; Smith, L; et al. (2000) The National Exposure Research Laboratory's consolidated human activity
database. J Expo Anal Environ Epidemiol 10:566-578.
Meranze, DR; Gruenstein, M; Shimkin, MB. (1969) Effect of age and sex on the development of neoplasms in Wistar rats
receiving a single intragastric instillation of 7,12-dimethylbenz(a)anthracene. Int J Cancer 4:480-486.
R- 5
-------
Miller, MD; Marty, MA; Arcus, A; et al. (2002) Differences between children and adults: implications for risk assessment at
California EPA. Int J Toxicol 21:403-418.
Morinello, EJ; Ham, AJL; Ranasinghe, A; et al. (2002a) Molecular dosimetry and repair of N2,3-ethenoguanine in rats
exposed to vinyl chloride. Cancer Res 62:5189-5195.
Morinello, EJ; Koc, H; Ranasinghe, A; et al. (2002b) Differential induction of N(2),3-ethenoguanine in rat brain and liver
after exposure to vinyl chloride. Cancer Res 62(18):5183-5188.
Murdoch, DJ; Krewski, D; Wargo, J. (1992) Cancer risk assessment with intermittent exposure. Risk Anal 12:569-577.
Naito, M.; Naito, Y; Ito, A. (1981) Effect of age at treatment on the incidence and location of neurogenic tumors induced in
Wistar rats by a single dose of N-ethyl-N-nitrosourea. Gann 72(4):569-577.
Newbold, RR; Bullock, BC; McLachlan, JA. (1990) Uterine adenocarcinoma in mice following developmental treatment
with estrogens: a model for hormonal carcinogenesis. Cancer Res 50:7677-7681.
Newbold, RR; Jefferson, WN; Padilla-Burgos, E; et al. (1997) Uterine carcinoma in mice treated neonatally with tamoxifen.
Carcinogenesis 18:2293-2298.
Newbold, RR; Hanson, RB; Jefferson, WN; et al. (1998) Increased tumors but uncompromised fertility in the female
descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis 19:1655-1663.
Newbold, RR; Banks, EP; Bullock, B; et al. (2001) Uterine adenocarcinoma in mice treated neonatally with genistein.
Cancer Res 61:4325-4328.
NRC (National Research Council). (1990) Health effects of exposure to low levels of ionizing radiation. Beir V. Committee
on the Biological Effects of Ionizing Radiation. Washington, DC: National Academy Press. Available online at
http://www.nap.edu/catalog/1224.html?se_side.
NRC (National Research Council). (1993). Pesticides in the diets of infants and children. Committee on Pesticides in the
Diets of Infants and Children. Commission on Life Sciences. Washington, DC: National Academy Press. Available online at
http://www.nap.edu/catalog/2126.html?se_side.
NRC (National Research Council). (1994). Science and judgment in risk assessment. Committee on Risk Assessment of
Hazardous Air Pollutants. Commission on Life Sciences. Washington, DC: National Academy Press. Available online at
http://www.nap.edu/catalog/2125.html.
NTP (National Toxicology Program). (1983) Carcinogenesis bioassay of L-ascorbic acid (Vitamin C) (CAS No. 50-81-7) in
F344/N rats and B6C3F1 mice (feed study). Research Triangle Park, NC: National Toxicology Program; TR-247.
NTP (National Toxicology Program). (1999) Toxicology and carcinogenesis studies of AZT and AZT/gamma-interferon in
B6C3FJ mice (gavage studies). Research Triangle Park, NC: National Toxicology Program; TR-469.
R- 6
-------
Nyandoto, P; Muhonen, T; Joensuu, H. (1998) Second cancer among long-term survivors from Hodgkin's disease. Int J
Radiat Oncol Biol Phys 42:373-378.
OECD (Organization for Economic Cooperation and Development). (1998) OECD guidelines for the testing of chemicals.
Paris, France: Organization for Economic Cooperation and Development.
Paulsen, JE; Steffensen, IL; et al. (2003) Age-dependent susceptibility to azoxymethane-induced and spontaneous
tumorigenesis in the Mini + mouse. Anticancer Res 23:259-265.
Peto, R; Gray, R; Brantom, P; et al. (1984) Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen
different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA
alone of the effect of age of starting (3,6, or 20 weeks) and of species (rats, mice, or hamsters). Lyon, France: IARC Sci
Publ; publication no. 57:627-665.
Pietra, G; Rappaport, H; Shubik, P. (1961) The effects of carcinogenic chemicals in newborn mice. Cancer 14:308-317.
Preston, DL; Pierce, DA; Shimizu, Y. (2000) Age-time patterns for cancer and noncancer excess risks in the atomic bomb
survivors. Radiat Res 154:733-734.
R Development Core Team (2003). R: a language and environment for statistical computing. Vienna, Austria: R Foundation
for Statistical Computing; ISBN 3-900051-00-3. Available online at http://www.R-project.org.
Renwick, AG. (1998) Toxicokinetics in infants and children in relation to the ADI and TDI. Food Addit Contam
15:S17-S35.
Rice, JM; Ward, JM. (1982) Age dependence of susceptibility to carcinogenesis. Ann NY Acad Sci 381:274-289.
Ries, LA; Kosary, CL; Hanke, BF; et al. (eds.) (1999). SEER Cancer Statistics Review 1993-1998. Bethesda, MD: National
Cancer Institute.
Robboy, SJ; Noller, KL; O'Brien, P; et al. (1984) Increased incidence of cervical and vaginal dysplasia in 3,980
diethylstilbestrol-exposed young women: experience of the National Collaborative Diethylstilbestrol Adenosis Project.
JAMA 252:2979-2983.
Rogers, S. (1951) Age of the host and otherfactors affecting the production with urethane of pulmonary adenomas in mice. J
ExpMed 93:426-449.
Russo, J; Wilgus, G; Russo, IH. (1979) Susceptibility of the mammary gland to carcinogenesis: I Differentiation of the
mammary gland as determinant of tumor incidence and type of lesion. Am J Pathol 96(3):721-736.
Sasaki, S; Kasuga, T; Sato, F; et al. (1978) Induction of hepatocellular tumor by x-ray irradiation at perinatal stage of mice.
Gann 69:451-452.
R- 7
-------
Scheuplein, R; Charnley, G; Dourson, M. (2002) Differential sensitivity of children and adults to chemical toxicity. I:
biological basis. Regul Toxicol Pharmacol 35:429-447.
Silberstein, GB. (2001) Tumour-stromal interactions: role of the stroma in mammary development. Breast Cancer Res
3:218-223.
Slikker W, 3rd, Mei N, Chen T. 2004. N-ethyl-N-nitrosourea (ENU) increased brain mutations in prenatal and neonatal mice
but not in the adults. Toxicol Sci 81(1): 112-120.
Terracini, B; Testa, M. (1970) Carcinogenicity of a single administration of N-nitrosomethylurea: a comparison of newborn
and 5-week-old mice and rats. Br J Cancer 24(3):588-598.
Terracini, B; Testa, MC; Cabral, JR; et al. (1976) The roles of age at treatment and dose in carcinogenesis in C3Hf/Dp mice
with a single administration of N-nitroso-N-methylurea. Br J Cancer 33(4):427-439.
Thompson, DE; Mabuchi, K; Ron, E; et al. (1994) Cancer incidence in atomic bomb survivors, Part II: solid tumors, 1958-
1987. RadiatRes 137:817-867.
Tomlinson, IP; Hampson, R; Karran, P; et al. (1997) DNA mismatch repair in lymphoblastoid cells from hereditary non-
polyposis colorectal cancer (HNPCC) patients is normal under conditions of rapid cell division and increased mutational
load. Mutat Res 383:177-182.
Toth, B. (1968) A critical review of experiments in chemical carcinogenesis using newborn animals. Cancer Research
28:727-738.
U.S. Cancer Statistics Working Group. (2002) United States cancer statistics: 1999 incidence. Atlanta, GA: Department of
Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. Available online at
http://www.cdc.gov/cancer/npcr/uscs/.
U.S. EPA (Environmental Protection Agency). (1986) Guidelines for mutagenicity risk assessment. Federal Register
51:34006-34012. Available online at http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=55907.
U.S. EPA (Environmental Protection Agency). (1991) Pesticide assessment guidelines, subdivision F, hazard evaluation:
human and domestic animals, series 84, mutagenicity, addendum 9. Office of Pesticides and Toxic Substances, Washington,
DC; EPA-540/09- 91-122. Available from: National Technical Information Service, Springfield, VA PB91-158394.
U.S. EPA (Environmental Protection Agency). (1994) Estimating radiogenic cancer risks. Washington, DC; EPA/ 402/R-
93/076. Available online at http://www.epa.gov/radiation/docs/rad-risk.pdf.
U.S. EPA (Environmental Protection Agency). (1996) Comparison of the effects of chemicals with combined perinatal and
adult exposure vs adult only exposure in carcinogenesis bioassays. Office of Pesticide Programs, Washington, DC.
Available online at http://www.epa.gov/scipoly/sap/1996/index.htm.
R- 8
-------
U.S. EPA (Environmental Protection Agency). (1999) Cancer risk coefficients for environmental exposure to radionuclides.
Federal Guidance Report No. 13. Washington, DC; EPA/402-R-99-001. Available online at
http://www.epa.gov/radiation/assessment/pubs.html.
U.S. EPA (Environmental Protection Agency). (2000a) Atrazine health assessment: Part B: Hazard assessment and review of
available studies. Office of Pollution, Pesticides, and Toxic Substandes, Washington, DC. Available online at
http://www.epa.gov/scipoly /sap/2000/june27/finalpartb_atz.pdf.
U.S. EPA (Environmental Protection Agency). (2000b) lexicological review of vinyl chloride. Integrated Risk Information
System (IRIS), National Center for Environmental Assessment, Washington, DC; EPA/635/R-00/004. Available online at
http://www.epa.gov/iris/toxreviews/1001-tr.pdf.
U.S. EPA (Environmental Protection Agency). (2000c) Risk information for vinyl chloride. Integrated Risk Information
System (IRIS), National Center for Environmental Assessment, Washington, DC. Available online at
http://www.epa.gov/iris/subst/1001 .htm.
U.S. EPA (Environmental Protection Agency). (2002a) Child-specific exposure factors handbook. National Center for
Environmental Assessment, Washington, DC; EPA/600/P-00/002B. Available from National Technical Information Service,
Springfield, VA, and online at http://www.epa.gov/ncea.
U.S. EPA (Environmental Protection Agency). (2002b) OPPTS harmonized test guidelines, series 870 health effects test
guidelines. Office of Pollution, Pesticides and Toxic Substances, Washington, DC. Available online at
http://www.epa.gov/opptsfrs/OPPTS.
U.S. EPA (Environmental Protection Agency). (2004) Guidelines for carcinogen risk assessment. Risk Assessment Forum,
National Center for Environmental Assessment, Washington, DC. Available online at
http://cfpub.epa. gov/ncea/raf/recordisplay .cfm?deid=5 5 907.
UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation (2000). Sources and effects of ionizing
radiation. 2000 Report to the General Assembly, with scientific annexes. New York, NY: United Nations Scientific
Committee on the Effects of Atomic Radiation. Available online at http://www.unscear.org/reports/2000_l.html.
Vesselinovitch, SD. (1983) Perinatal hepatocarcinogenesis. Biol Res Pregnancy Perinatol 4(l):22-25.
Vesselinovitch, S. D; Mihailovich, N. (1983) Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse.
Cancer Res 43:4253-4259.
Vesselinovitch, SD; Rao, KV; Mihailovich, N; et al. (1974) Development of broad spectrum of tumors by ethylnitrosourea in
mice and the modifying role of age, sex, and strain. Cancer Res 34(10):2530-2538.
Vesselinovitch, SD; Kyriazis, AP; Milailovich, N; et al. (1975a) Conditions modifying development of tumors in mice at
various sites by benzo(a)pyrene. Cancer Res 35:2948-2953.
R- 9
-------
Vesselinovitch, SD; Rao, KV; Mihailovich, N. (1975b) Factors modulating benzidine carcinogenicity bioassay. Cancer Res
35(10):2814-2819.
Vesselinovitch, SD; Rao, KV; Mihailovich, N. (1979) Neoplastic response of mouse tissues during perinatal age periods and
its significance in chemical carcinogenesis. NCI Mongraph 51:239-250.
Vesselinovitch, SD; Rao, KV; Mihailovich, N. (1979a) Neoplastic response of mouse tissues during perinatal age periods.
NCI Mongraph 51:239-250.
Vesselinovitch, SD; Rao, KV; Mihailovich, N. (1979b) Transplacental and lactational carcinogenesis by safrole. Cancer Res
39(11):4378-4380.
Vesselinovitch, SD; Koka, M; Mihailovich, N; et al. (1984) Carcinogenicity of diethylnitrosamine in newborn, infant, and
adult mice. J Cancer Res Clin Oncol 108:60-65.
Vessey, MP. (1989) Epidemiological studies of the effects of diethylstilboestrol. Lyon, France: IARC Sci Publ; publication
No 96, pp. 335-348.
Waalkes, MP; Ward, JM; Diwan, BA. (2003) Transplacental carcinogenicity of inorganic arsenic in the drinking water:
induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. Toxicol Appl Pharmacol 186:7-17.
Walters, MA. (1966) The induction of lung tumours by the injection of 9,10-dimethyl-l,2-benzanthracene (DMBA) into
newborn suckling and young adult mice. A dose response study. Br J Cancer 20(1): 148-160.
Waters, MD; Stack, HF; Jackson, MA. (1999) Short-term tests for defining mutagenic carcinogens. In: McGregor, DB; Rice,
JM; Venitt, S; eds. The use of short term tests for carcinogens and data on genetic effects in carcinogenic hazard evaluation.
Lyon, France: International Agency for Research on Cancer. Publ. No. 146, pp. 499-536.
Whysner, J; Williams, GM. (1996) Saccharin mechanistic data and risk assessment: urine composition, enhanced cell
proliferation, and tumor promotion. Pharmacol Ther 71:225-252.
Zartarian, VG; Ozkaynak, H; Burke, JM; et al. (2000) A modeling framework for estimating children's residential exposure
and dose to chlorpyrifos via dermal residue contact and non-dietary ingestion. Environ Health Perspect 108:505-514.
R-10
------- |