&EPA
US EPA Office of Research and Development
          United States
          Environmental Protection
          Agency
            Office of Research and
            Development
            Washington DC 20460
EPA/600/R-00/105
December 2000
Summary of the
Workshop on Information
Needs to Address
Children's Cancer Risk

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                                   EPA/600/R-00/105
                                   December 2000
Summary of the Workshop on
Information Needs to Address
    Children's Cancer Risk
  National Center for Environmental Assessment
     Office of Research and Development
     U.S. Environmental Protection Agency
          Washington, DC 20460
                                Printed on Recycled Paper

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                                      NOTICE
       This document has been reviewed in accordance with U.S. Environmental Protection
Agency (EPA) policy and approved for publication.  Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.

       This report was prepared by Eastern Research Group, Inc. (ERG), an EPA contractor
(Contract No. 68-C-98-148, Work Assignment No. 2000-01) as a general record of discussions
during the Workshop on Information Needs to Address Children's Cancer Risk.  This workshop
was co-sponsored by EPA's National Center for Environmental Assessment and National
Institutes of Health's National Institute of Environmental Health Sciences.  As requested by
EPA, this report captures the main points and highlights of discussions held during plenary
sessions. The report is not a complete record of all details discussed nor does it embellish,
interpret, or enlarge upon matters that were incomplete or unclear.  Statements represent the
individual views of each workshop participant; none of the statements represent analyses by or
positions of the NIEHS or the EPA.
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                              CONTENTS
                                                                   Page
INTRODUCTION     	       j

THURSDAY, MARCH 30 	  2

     WELCOME AND CHARGE TO WORKSHOP PARTICIPANTS
     William'Farland and Michael Firestone	 J.........             2

     SENSITIVITY OF CHILDREN TO ENVIRONMENTAL TOXICANTS
     Lynn Goldman  	            4

           Discussion 	            6

     CHILDREN'S ENVIRONMENTAL HEALTH
     Lynn Goldman	          ,             g

           Discussion 	_          9

FRIDAY, MARCH 31  	 13

     EXPOSURE OF CHILDREN TO ENVIRONMENTAL TOXICANTS
     Philip Landrigan	'...'.'	        13

     TOPIC 1: CURRENT AND PROPOSED APPROACHES TO ASSESSING
     CHILDREN'S CANCER RISK
     William Farland	.....'.	                16

           Discussion	 .i	                  20

           Facilitated Discussion ...;........	            21

           Discussion  	            24

     TOPIC  2: ENHANCED USE OF TEST DATA RELATED TO CHILDREN'S CANCER
     RISK
     Rochelle Tyl	                  26

           Facilitated Discussion	      27

           General Discussion	          28
                                  m

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    TOPIC 3: FUTURE DIRECTIONS FOR TOXICOLOGY TESTING TO ADDRESS
    CHILDREN'S CANCER RISK
    RethaNewbold	  32

          Facilitated Discussion 	  33

          Discussion 	  35

    TOPIC 4: EPIDEMIOLOGIC/MOLECULAR EPIDEMIOLOGY INFORMATION TO
    ADDRESS CHILDREN'S CANCER RISK
    Leslie Robison  		,	•		•	  36

          Facilitated Discussion 	  38

          General Discussion	  40
     WORKSHOP SUMMARY
     George Lucier   	
42
          Discussion 	 43

APPENDIX A:  WORKSHOP PARTICIPANTS 	A-l

APPENDIXB:  LIST OF OBSERVERS	 B-l

APPENDIX C:  MEETING AGENDA	 C-l

APPENDIXD:  CHARGE TO PARTICIPANTS	•	 D-l

APPENDIX E:  OVERHEADS USED IN THE PRESENTATIONS	 E-l

APPENDIX F:  LIST OF BACKGROUND MATERIALS PROVIDED TO
             PARTICIPANTS PRIOR TO THE MEETING	 F-l
                                  IV

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INTRODUCTION

      On March 30-31, 2000, the U.S. Environmental Protection Agency (EPA)'s Office of
Research and Development and the National Institute of Environmental Health Sciences
(NIEHS) cosponsored a workshop entitled "Information Needs to Address Children's Cancer
Risk." The workshop focused on a discussion of children's cancer risk assessment and related
data needs to address issues that were raised during public review of The Agency's 1999 Draft
Revised Guidelines for Carcinogen Risk. These issues include:
•     Characterizing the ideal data set to adequately address children's cancer risk.
•     Proposed approaches to using available data in the absence of the ideal data set.

      The background for discussions at the Workshop is the reality that chemical-specific data
are often lacking to specifically address children's cancer risk from environmental chemical
exposures. Consequently, the assessment of children's risk is currently addressed by evaluations
of traditional bioassays in mature animals, comparative biochemistry and physiology between
adult and developing animals and humans, and public-health-protective default positions in the
absence of child-specific data. The Workshop focused on four topics areas:

•     Topic 1: Current and Proposed Approaches to Assessing Children's Cancer Risk.
•     Topic 2: Enhanced Use of Test Data Related to Children's Cancer Risk.
•     Topic 3: Future Directions for Toxicology Testing to Address Children's Cancer Risk.
•     Topic 4: Epidemiological/Molecular Epidemiology Information to Address Children's
      Cancer Risk.

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Summary ofEPA Workshop on Information Needs to Address Children's Cancer Risk
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      The cosponsors invited the participation of leaders in the area of human health testing,
research, and assessment who represented the pediatric, lexicological, and risk assessment
communities. The invited participants addressed not only the induction of childhood cancer, but
also increased risks of cancer during adulthood as a consequence of childhood exposure.
Observers participated in the discussions of issues specific to topic areas and contributed
comments during periods of general discussion.

      This report  summarizes the Workshop discussions. Appendix A lists the Workshop
participants, and Appendix B provides a list of observers. The meeting agenda and charge to
participants can be found in Appendices C and D, respectively. Appendix E contains copies of the
overheads used in  the presentations. Appendix F lists the background materials provided to
participants prior to the meeting.
 THURSDAY, MARCH 30
 WELCOME AND CHARGE TO WORKSHOP PARTICIPANTS
 William Farland and Michael Firestone

       William Farland, Director of EPA's National Center for Environmental Assessment, and
 George Lucier of NffiHS welcomed the participants and observers on behalf of the sponsoring
 Agencies.

       Michael Firestone of EPA's Office of Children's Health Protection noted that the intent of
 EPA and NffiHS in sponsoring the Workshop was not to seek recommendations or reach
 consensus decisions. The main purpose, he said, was to obtain individual views and perspectives
 on children's cancer risk assessment and related data needs, and to address issues that have arisen
 during review of EPA's Draft Revised Guidelines for Carcinogen Risk Assessment. He said

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Workshop participants should focus on how discussions might have an impact on the ongoing

effort to revise EPA's Cancer Guidelines. He listed the specific issues that would be the focus of

discussion during the Workshop (see "Charge to Workshop Participants" in Appendix D and

"Charge to the Children's Cancer Workshop Participants" in Appendix E):
      Characterizing the content of the ideal data set to adequately address children's cancer
      risk, with a focus on data needed for assessing the impact of childhood (including in
      utero) exposures to carcinogens and the issues related to hazard identification and dose-
      response analyses.

      Addressing not only induction of childhood cancer, but also increased risks of cancer
      during adulthood resulting from'childhood exposure.

      Considering how current bioassay testing protocols might be redesigned to better answer
      questions related to children's cancer risk and what additional types of data might be
      brought to bear on children's cancer risk assessment.

      Defining what are the elements of a "cogent biological rationale," as presented in the draft
      revised cancer guidelines, for addressing modes-of-action for children's cancer.

      Answering whether and how a "cogent" rationale that is sufficiently health-protective of
      children can be made based on the kinds of data that are typically collected by and
      available to Federal and State health science agencies at the present time.

      Defining what additional data, such as cancer mode-of-action and comparative
      pharmacokinetics and pharmacodynamics in adults and children, might be useful in
      developing a "cogent" rationale.

      Addressing whether the assessment of children's risks, as it is currently conducted by
      evaluations of traditional bioassays  in mature animals using sensitive responders, is
      sufficiently public-health-protective in the absence of child-specific data.
      In discussing these points, participants noted that the Workshop's purpose was not to

describe idealized research protocols that might be developed to provide all data necessary to

characterize children's cancer risks, and urged that discussions remain focused on the questions

of how best to use available methods and data to address children's cancer risks. An observer

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
noted that the last issue—whether current use of traditional bioassays in mature animals is
sufficiently protective in the absence of child-specific data—might imply a simple "yes" or "no"
answer, and urged that the Workshop go beyond that answer. Abe Tobia asked whether the
Workshop would be involved in looking at design of future studies, noting that it would require a
significant effort. Lynn Goldman replied that the Workshop's charge allows discussion of new
study designs, but emphasized the need to consider current issues as expressed in the draft
Guidelines.  George Lucier encouraged Workshop participants not to get bogged down with a
great deal of detail and specificity when addressing future needs. He also asked them to
remember, during the discussions, that the revised Guidelines should be able to stand the test of
time and adequately capture the need for new approaches and strategies to be used in toxicology
testing as it  relates to childhood cancer. Abe Tobia repeated his view that the Workshop should
focus on what is currently being done and potentially relevant to the current Guidelines. William
Farland noted that the Workshop schedule included an opportunity to discuss possible directions
for future research. He suggested that specific changes in protocol should be addressed by a
separate panel or Workshop in the future.

SENSITIVITY OF CHILDREN TO ENVIRONMENTAL TOXICANTS
Lynn Goldman

       Dr. Goldman noted that the Workshop faced a challenging task in addressing childhood
 cancer and  its potential causes as well as children's exposures to carcinogens, which are two
 separate but important issues in terms of risk assessment. She said Workshop participants should
 be mindful  of the fact that EPA and other government agencies represented at the Workshop
 make decisions each day with respect to cancer risks and that the goal of the Workshop was to
 make positive contributions to those decisions. She noted that the purpose of the Workshop was
 not to specifically evaluate EPA's Cancer Risk Assessment Guidelines or to replace other
 mechanisms for review of the Guidelines. Dr. Goldman presented an overview of issues related
 to childhood cancer:

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
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•     They have a low rate of occurrence and there is uncertainty about trends in occurrence.
•     Childhood cancers are limited to a few unique types that are found in children but not
      adults and tend to reflect fetal derivation of cells and prenatal exposures.
•     Most childhood cancers have short latency periods; many are characterized by known
      genetic and familial associations.
•     There is a high probability of genetic/environmental interactions in children's
      susceptibilities to cancer.

      Dr. Goldman noted that childhood cancer mortality has been decreasing but that there
were increases in the rates of acute lymphocytic leukemia and brain cancers among children
1980s. Some research suggests that childhood is a time of greater susceptibility to cancer, Dr.
Goldman said. The possibility that children and the developing fetus face risks not seen in adults
is supported by examples such as in utero exposure to DBS during a specific period of fetal
development and the subsequent-occurrence of vaginal cancer and diseases that resemble birth
defects. This suggests a hormonally driven process that changes cell differentiation. Other
examples of childhood-specific risks are incidences of radiation-induced cancers that have a
short latency and suggest increased risk during developmental periods of rapid cell division.
Exposure to tobacco during periods of rapid cell division may also explain observed relationships
between age of smoking initiation and lifetime risk for lung cancer and a persistence of risk after
people stop smoking. Although only a small percentage of cancers are due solely or in part to
environmental exposures, these cancers may account for 5-25 percent of annual cancer deaths,
and therefore represent a large public health burden. Dr. Goldman suggested that, in considering
the adequacy of the rodent bioassay model, the Workshop's discussions of childhood
susceptibility should focus on:
      Genetic susceptibilities, including inherited predisposition and polymorphisms that result
      in pharmacokinetics that affect dose.

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•     Reduced latency that results from rapid tissue growth during childhood.
•     The persistence of effects due to mutations or alterations of cell differentiation.
•     Nutritional factors.
      Hormonal factors, including the influence of exogenous hormones such as DBS.

      Dr. Goldman asked participants and observers to respond to these points and to add other
issues that would be relevant to the Workshop's goals of considering how the EPA Guidelines
can properly address children's cancer risks.

Discussion

      Rochelle Tyl said the Workshop should consider the repair capacity of a young organism
compared with an older more developed organism, the differences in metabolism between
prenatal or perinatal animals and adult animals, and clearance. These issues may reveal reasons
why the young may be more susceptible, Dr. Tyl said.

       Paul Foster recommended consideration of the developmental "window" during which
exposure occurs. Chris Portier said that  consideration of cancers resulting from viral exposures
also should be considered. Dr. Portier and Dr. Goldman both noted that the interaction of
multiple factors is an important consideration but one that would be very difficult to examine in
bioassays. David Wallinga suggest adding consideration of immature immune systems and the
 protective factors such as the the patency of the blood-brain barrier in immature animals. Lauren
 Zeise noted that certain exposure factors should be considered; she cited as an example the
 increased exposure to contaminants in drinking water of a child being fed infant formula.

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      Frederica Perera said that racial, ethnic, or cultural variability may play a role in
susceptibility but cannot be modeled using rodent bioassays. Joseph DeGeorge observed that
possible genetic predispositions and racial or ethnic variabilities may play as large a role in adults
as in children, and might therefore be beyond the scope of the Workshop. Dr. Perera and Dr.
Goldman responded that genetic predisposition may play an important role in cell growth and
differentiation and therefore might be particularly important during periods in life when there is
rapid cell growth. George Lucier said there would be a mushrooming of information about the
relationship between genetic predispositions and diseases that are easily detectable,  such as
childhood cancers. How to use that information  in childhood cancer risk assessments is going to
be very difficult, he said. Dr. DeGeorge repeated his observation that genetic predispositions and
racial or cultural factors do not represent defining factors between the effects of fetal or
children's exposures and adult exposures, and are a bigger issue than the Workshop's focus on
childhood cancer risks. Mark Miller noted that there are genes that may be associated
carcinogenicity or susceptibility in childhood but are not associated with adult cancers. Chris
Portier said that genetic predisposition is an important area to explore for differences between
adults and children. For example,  genes that "turn on" during a particular stage of development
may point out windows of opportunity. Polymorphisms in those genes coupled with exposure at a
certain time could have a serious effect. Because these genes tend to be selected out of the
population, it is very difficult to gather information without specifically looking for  it, Dr. Portier
said.
      Michael Thun said that an underlying theme in the discussion seemed to be the question of
the conditions under which a study in rodents can give the wrong answer to questions about
childhood cancer. For example, he noted, a study in animals may not show a problem but under a
special circumstance such as nutritional deficiency or the presence or absence of a polymorphism
there may be a problem. The number of possible permutations of conditions that would need to
be studied is huge, and it will be a long time until there is a bioassay that will tell whether there is

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a problem in all subjects. EPA now factors in a protective margin—the upper 95 bound—to cope
with this problem, but from the point of view of a biologist, Dr. Thun said, all bioassays provide
incomplete information.

       Lauren Zeise suggested that another issue to consider is timing. Exposure early in life has
more time to interact with other exposures to cause cancer, but timing is not now addressed in
Guideline default procedures, she said.

       Leslie Robison noted that children's cancers tend to be very specific types of cancers, and
said that extrapolating from data acquired in animal models may not have anything to do with the
induction of the unique spectrum of cancers  that occur in children.

       Abe Tobia said that 90-day animal assays may not reveal problems but do not allow for a
 pathological continuum that leads to some childhood cancers and, from that perspective, short
 term studies may yield false negative data. A very important issue, he said, is the need to conduct
 a long-term definitive study that detects these cancers and can be used to determine whether that
 relates back to childhood. Rochelle Tyl said that the key problem with 90-day studies and chronic
 studies is that exposure starts in animals that have gone through puberty and are essentially
 adults. This misses the most vulnerable stages of development for some cancers, and even 2-year
 or 3-year bioassays that begin exposure at 6 to 8 weeks will not detect cancers resulting from in
 utero or lactational exposure.

 CHILDREN'S ENVIRONMENTAL HEALTH
 Lynn Goldman

        It is crucial to recognize that children are not little adults and are exposed in ways that
 have no parallel in adult life. For example, breast-feeding is an exposure route only for infants.
 Moreover, a child's metabolism may be more or less capable than an adult's of breaking down,

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inactivating, or activating toxic substances. The rapid growth and development of organ systems
that takes place during childhood increases the vulnerability of children, who also have more
years of future life in which diseases with long latency periods might develop.

      Children's exposure to dioxin is more than two orders of magnitude greater during their
first years of life, when they are breast fed, than later in life, Dr. Goldman pointed out. Intake
rates for water, food, and air, per kilogram of body weight, are greater for children than for
adults, and some routes of exposure are different in children. Because infants, toddlers, and
preschool-age children spend much of their time on the floor or on the ground and use their
hands and mouths to explore these environments, they are exposed in different ways to different
contaminants than are adults.  In addition, children's diets frequently focus on certain foods that
are relatively uncommon in adult diets, she noted.

Discussion
      George Lucier asked what types of information are now available that indicate the relative
magnitude of children's body burdens of toxics compared with those of adults. Dr. Goldman
replied that there is very little available. William Farland said that the EPA was initiating studies
of very small populations as a first step in measuring national human exposures, and is
participating in planning stages of a longitudinal birth cohort study that will provide more
detailed information on exposure and body burden. Chris Portier said that measurement of body
burdens would provide more relevant information than measurement of exposure and intake. Dr.
Goldman said that there are very few animal studies that provide information relating body
burden in mothers to body burden hi the fetus. Joseph DeGeorge noted that intake rates as well as
metabolic elimination rates change rapidly throughout childhood. Dr. Goldman noted that animal
studies may not be able to accurately model these changes in humans. Dr. DeGeorge said that the
Food and Drug Administration had conducted surveys of literature to obtain information on

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organ development and profiles of metabolism as it changes through childhood. The data are
difficult to find and, he added, it is very difficult to develop a parallel between adult animals and
adult humans, and even more difficult to find juvenile animal models that represent juvenile
humans. Dr. Farland suggested that pharmacokinetic modeling may offer a better understanding
of dose in both humans and animals. Refining these studies, he said, will improve the ability to
understand the effects of target doses on target tissues. This would eliminate the sometimes
misleading reliance on measuring exposure and intake levels.

       f rederica Perera noted that the multiple or repeated exposures lead to complex
interactions that are not well understood, and that these interactions may have different effects in
children than in adults. David: Wallinga said that, unlike adults, children have a fairly predictable
set of exposures through types of food or specific medications, but these predictable mixtures
have not been considered in risk assessment. Lauren Zeise suggested that studying body burdens
of compounds that act by similar mechanisms may be more valuable than concentrating on the
body burden of a single compound, particularly when determining whether the observed dose-
response should be considered in a linear or nonlinear way.

       Joseph DeGeorge noted that existing data acquired through neonatal rodent assays
demonstrates that juvenile animals are more susceptible than adults to carcinogens. There is no
need to develop new tests to detect differential sensitivity. What is needed, he said, is an
understanding of why there is greater sensitivity  and how it applies to humans. George Lucier
noted that for a few effects, such as breast cancer, information exists to show that animal data can
be applied to human risk. Using lessons from these few models that have been well explained
would help develop other mechanistic animal models that can be applied to humans. Dr.
DeGeorge noted that more than 90 chemicals have been tested in juvenile animals, and a
neonatal mouse assay, which can identify tumor effects within a year, is now being studied as an
alternative to  the two-year adult bioassay. Dr. Portier noted that much of the published data is
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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
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from studies that rely on one or two doses and does not tell very much about the curvature of the
dose-response. This is important, he said, because there may be chemicals that cause adult cancer
through a very nonlinear mechanism but have a linear mechanism in infants. Dr. Goldman
observed that it is important to fully explore the issue of susceptibility versus exposure, because
differences in  susceptibility would result in different dose-response curves in children and adults
with the same  exposures.

      Dr. Portier noted that the same mechanism of action can have different effects at different
ages or. stages  of development. For example, he said, a carcinogen may be activated by
metabolism but is then mediated by an organism's repair capacity.  If that capacity is low in the
child and high in the adult, there might be linearity in the child and nonlinearity in the adult, even
though the same mechanism is involved.

      Chris Wilkinson said the Workshop should recognize that the EPA's current draft
represents a good set of cancer risk assessment guidelines that should not be further delayed by
extensive discussion of specific children's cancer issues. These issues  are very  important, he
said, but should not become a barrier to finalizing the Guidelines. He suggested that the
Workshop's goal should be to identify four or five major factors that could be incorporated into
the Guidelines and move forward. Dr. Farland noted that the Workshop has been charged
specifically to  address childhood sensitivity and to assure that the guidance put forward is public-
health-protective. Abraham Tobia said the Workshop should focus on  identifying a few topics
that can be fully explored. He said the Guidelines represent a  solid framework and should be
implemented, and that fuller discussion of other issues  will come later. It is important that the
regulated community understand what kind of information it is expected to generate.
      David Goldsmith said that susceptibility must be looked at as a result of interactive
effects. He also noted that it is necessary to understand the role of changes, in immunologic
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competence as a child matures. Sam Kacew said that the role of lactation and breast feeding,
which had been mentioned as means of exposure, should also be considered in terms of
development of the immune system. He suggested that the Workshop also consider other
nutritional factors, both protective and harmful. Paul Foster said that fetal dosimetry and
lactational transfers are critical measures that should be developed to provide first-hand practical
information on how much of a chemical crosses the placenta and how much is transferred in
milk.

       Jeanette Wiltse said that information about mode of action from a 2-year bioassay or from
a 2-generation study is not relevant when exposure begins in utero. She suggested that
Guidelines should encourage studies on mode of action in the very young animal, which is not
part of the standard protocol. Dr. Tobia said that the regulated community wants to provide
information that will be used in the risk assessment process. Sometimes that information is
outside the required data but may help make a case for a different way of modeling a carcinogen.
But, he added, unless the information is used in decision-making there is no benefit to doing the
work necessary to gather it. Dr. Farland said that relevant information may be available in data
 that are routinely collected for endpoints other than children's cancer. Dr. Portier said that it is
 important to determine what kind of information is necessary to understand the mode-of-action
 issue in children, and that type of information cannot be derived from current data on adult
 animals.  Philip Landrigan said that it is simply not possible to extrapolate from the adult
 experience to predict what is going on in the neonate or the infant. He urged that the Workshop
 focus on the role of the Guidelines as a means to protect human health. He said that this goal is
 best achieved by assessing the risks in children, who are  the most vulnerable segment of the
 population.
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FRIDAY, MARCH 31

EXPOSURE OF CHILDREN TO ENVIRONMENTAL TOXICANTS
Philip Landrigan

      Workshop chair Philip Landrigan opened the Workshop's second session by observing
that the explicit goal of the Guidelines should be prevention of disease, not detailed
understanding of mechanisms of action. Risk assessment should be considered in a public health
context, he said, and he noted that two centuries of medical advances had dramatically reduced
the incidence and mortality of infectious diseases in the U.S. During the past 50 years the number
of synthetic chemicals entering the environment has increased enormously, and few of these
chemicals have been subjected to toxicity testing. To discuss detailed mechanisms of action for a
few chemicals while basic toxicity data are lacking for many chemicals is putting the cart before
the horse, he said.

      Patterns of disease in children are changing in ways that are not well understood, Dr.
Landrigan said, noting that asthma, childhood cancers, congenital urinary tract defects, and
testicular cancer in young men have increased steadily since the early 1970s. Ten years ago the
National Academy of Sciences (NAS) Committee on Pesticides and Children was charged to
answer three questions that are  directly relevant to the Workshop's purpose, Dr. Landrigan said.
The questions are:

•     Are children more heavily exposed than adults?
•     Are children more susceptible to toxicity than adults?
      Do current laws and decisions protect children?
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      Childhood exposure to carcinogens is vastly different and greater by orders of magnitude
than adult exposure. Moreover, Dr. Landrigan noted, children live and play on the floor and often
put their hands in their mouths, and their exposures come from a wider variety of environmental
sources than do adults'. Children are also more vulnerable to environmental toxicants, as
indicated by such examples as children's increased risk of cancer following exposure to
nitrosamines and vinyl chloride, decreased ability to detoxify organophosphates, increased
susceptibility to lead and alcohol (fetal alcohol syndrome), and the relationship of DBS and
adenocarcinoma of the vagina. Such data led the NAS Committee to note that "children are not
little adults" and to conclude that:

      Children's exposures to pesticides are greater pound-for-pound than those of adults.
      Children are less well able than adults to detoxify most pesticides.
      Children's developing organ systems are highly vulnerable to pesticides.
      Children have more years of future life in which to develop chronic disease triggered by
      early exposure.

        Dr. Landrigan emphasized that the last point is important to the Workshop's discussion
because, although childhood cancers are relatively rare, exposures during  childhood increase the
risk of adult cancer. Dr. Landrigan cited the NAS committee conclusion that "compared to late-
in-life exposures, exposures to pesticides in early life can lead to effects that are expressed only
after long latency periods have elapsed. Such effects include cancer, neurodevelopmental
impairment and immune dysfunction." The NAS committee concluded that traditional risk
assessment does not reflect the complexity of children's exposures to carcinogens, is limited to
study of too few chemicals, and largely is based on exposures of adult animals.

        Commenting on earlier Workshop discussion suggesting that consideration of children's
 cancer risks might add a complicating layer of complexity to risk assessment, Dr. Landrigan said
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that children's risk should be the core of the risk assessment Guidelines. Risk assessment in a
public health context has as its goal the protection of the most vulnerable, Dr. Landrigan said,
and therefore must be based on risks to children. Dr. Landrigan noted that the NAS committee
made general and specific recommendations that were incorporated into the 1996 Food Quality
Protection Act and led to EPA's 1996 declaration that children's health is a specific focus of the
Agency's environmental health plan.

       Dr. Landrigan referred to a recent journal article (Faustman, et al.) in which the authors
discuss- consideration of children's susceptibility in an overall framework for human risk
assessment and say "An important public health challenge has been the need to protect children's
health. To accomplish this goal, the scientific community needs scientifically based child-
specific risk assessment methods." That comment, Dr. Landrigan said, should set the stage for
the Workshop discussions. Dr. Landrigan said that defaults and safety factors have become a
major component of pesticide regulation, and are applied when it is determined through research
that infants and children are more vulnerable than adults to a compound or, more commonly,
when there no child-specific data are available. He said defaults are not sufficiently emphasized
in the Carcinogen Risk Assessment Guidelines and suggested that there be explicit mention of
defaults in the Guidelines. In closing, Dr. Landrigan said that despite the work already done to
draft the Guidelines,  they should be  fundamentally rewritten as a concise document that clearly
states goals and objectives, cites previous work, describes methods, and concludes with a
discussion and references. Other work done to date would be included as an appendix, he
proposed.
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TOPIC 1: CURRENT AND PROPOSED APPROACHES TO ASSESSING CHILDREN'S
CANCER RISK
William Farland

       Dr. Farland said the EPA is a public health agency with its principal focus on disease
prevention. To this end, he said, the Agency's draft Guidelines have been developed to protect
the most vulnerable populations and most sensitive individuals. This includes an explicit
consideration of children and their unique vulnerabilities, Dr. Farland noted. He reviewed the
development of Cancer Risk Assessment Guidelines and noted that they serve not only to guide
risk management but to identify research needs and to advance the science of risk assessment,
particularly as it might be applied to children and other vulnerable populations. As a result, he
said, cancer risk assessment is an iterative process and the Guidelines are the product of
continuous dialogue and reevaluation driven by new data and models. He noted that the
 Guidelines are the result of interagency colloquia, peer consultation and review, three reviews by
 EPA's Science Advisory Board, multiple interagency reviews, and public comment. He said the
 Agency Risk Assessment Guidelines are:

        Statements of Agency policy regarding principles, general approaches, preferences, and
        default assumptions that will be applied in Agency risk assessment.
 •      Not a cookbook.
 •      Not a regulation.

        The first Agency carcinogen Guidelines were issued in 1976, and new Guidelines based
 on the "state of the science'-' were issued in 1986. The 1986 Guidelines were flexible, Dr. Farland
 said, but provided little guidance on when or how to depart from default assumptions and
 therefore did not provide much incentive to collect better data. Moreover, they did not include
 specific consideration of children. These shortcomings led the Agency to initiate the revision of
 the Guidelines. The new directions for risk assessment guidelines:
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•      Emphasize full characterization.
•      Expand the role of mode of action information and, therefore, biomarkers.
•      Use all information to design dose-response approach.
•      Incorporate a two-step dose-response assessment.

       The two-step dose-response assessment first considers information within the range of
observation and then explicitly considers moving from these observations into the range of
inference to make, in some cases, decisions that are not testable. The Draft Carcinogen Risk
Assessment Guidelines reflect a mode-of-action analysis based on physical, chemical, and
biological information rather than a detailed mechanism-of-action analysis that may delay action
because there would never be complete information. Risk assessment has evolved from hazard
identification that relies on traditional toxicologic testing to hazard characterization through
evaluation of mechanisms and biologically based models ranging from new strains of rodents to
mathematical models, Dr. Farland said. Mode-of-action considerations involve asking:

•      How does the chemical produce its effect?
•      Are there mechanistic data that support this hypothesis?
•      Have other mechanistic hypotheses been considered and rejected?

Mode-of-action data is used in dose-response assessment to:

•      Construct a biologically-based or case-specific model.
•      Link the dose-response curve for precursor effect to dose-response curve for tumor effect.
•      Use dose-response for other effects in lieu of that for tumor effect if it is judged to be a
       better measure of potential risk.
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       Inform assessment of possible dose-response in range of extrapolation.

In the range of extrapolation, Dr. Farland said, the dose-response assessment is:
       Linear if:
•      DNA-reactive or other evidence supports linearity.
       Not DNA-reactive but there are insufficient data to characterize a non-linear mode of
       action.
       Non-linear if:
       not DNA reactive or otherwise linear, and sufficient data exist to characterize a non-linear
       mode of action.
       Both if:
       There is differing activity at different sites.
       Linear and non-linear approaches are needed to explain complex activity.

       Non-linear includes a margin of exposure approach that is new to the Guidelines, Dr.
 Farland said. This is an evaluation of how close the available human or animal data are to the
 exposure of interest. It allows for a judgment as to whether or not the increment of exposure is
 large enough to give regulators confidence that they are being public-health-protective.

        The linear approach is public-health-conservative because, by using an upper bound on
 risk, it allows the Agency to project several orders of magnitude from observed data without
 making adjustments to account for human variability, Dr. Farland said. This is in agreement with
 the National Research Council's suggestion that pharmacokinetic models or scaling adjustments
 be applied to account for species differences in toxicokinetics, differences in exposure rate, or the
 magnitude of exposure in a population being considered. Low-dose extrapolation is conducted at

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the point of departure—the lower 95 percent confidence limit on the lowest dose associated with
tumor response—determined under standard conditions on test rodents considered to be stressed,
not average. The straight-line extrapolation achieves risk estimates similar to those derived by
the procedures described in the 1986 guidelines, and overestimates risk at low doses. The linear
approach assures that risk to  the population is not Underestimated and thereby protects public
health, Dr. Farland said.

       Generalized models are not able to account for differences in risk due to human
variability, Dr. Farland noted. Therefore a margin  of exposure analysis is used when a nonlinear
default is supported. If no agent-specific data suggest a differential response in children, the
human variability factor is applied with adjustment to account for dose in children, but with no
other additional factors to protect children, he said. The proposed Guidelines' approach to
children's risk incorporates:

•      Potential differences in exposure, dose, and response between children and adults.
•      A case-by-case approach based on weight of evidence.
•      Default science policy positions and procedures to be used in the absence of data.

       The Guidelines call for separate evaluation when data suggest increased sensitivity to
exposures that occur early in life and include an illustration of how these data can be applied to
calculate both adult and childhood-specific unit risk estimates. In addition, Dr. Farland said, this
approach provides a lifetime  risk estimate that considers, both independently and additatively,
increased childhood risk as well as effects in  adults due to early-in-life exposure. Because slope
factors and unit risk for lifetime exposure  are based on adult data, the Guidelines adjust adult unit
risk to account for differences in dose between adults and children, Dr. Farland said. These
adjustments involve:
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       Default procedures for adult-to-child risk adjustments based on differences in dose:
              Oral dose factor—no adjustment is proposed.
              Inhalation unit risk (gases)—adjustment based on body weight and breathing rate.
              Drinking water unit risk—adjustment based on body weight and drinking water
              rate.
•      Determining guidance for inhaled particles and dermal exposure.
       Asking whether these default procedures are appropriate and incorporating new data.

       In considering dose-response in children,  if a postulated mode-of-action is supported for
adults but not for children, a linear low-dose default will be applied as a default for the general
population, including children. This approach accounts for the possibility of increased risk to
children while possibly overestimating adult risk, thereby providing public-health-protective
estimates based on possible effects in the most sensitive population, Dr. Farland said. When there
is no available information on mode of action in  children, or when there is no cogent biological
rationale that supports the assumption that mode of action in children is the same as in adults, the
postulated mode of action is not considered applicable to children.

        Dr. Farland said the Agency hopes to publish the new Guidelines early in 2001, and will
 include a shorter supplementary guidance focused on assessment of children's risk.
 Discussion
        George Lucier asked how much flexibility the Guidelines would allow in order to
 accommodate factors such as differences between the ways in which children and adults are
 exposed or interspecies variations such as the 100-fold difference in half-life of dioxin in humans
 compared with rodents. The lack of information on such issues is a significant problem facing
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implementation of the Guidelines, he said. Dr. Farland noted that the Guidelines must calculate
human equivalent dose from animal models. Individual cases such as dioxin would have to be
considered separately and explicitly, he said, but the standard human equivalent dose approach
includes body weight to the three-quarters power as a scaling factor based on metabolic rate.
Exposures coming from different sources are accounted for, in part, by the Guidelines'
consideration of background exposure when calculating exposure relative to the dose-response
curve, Dr. Farland said.

       Lynn Goldman said the Guidelines should clearly describe the mode of action default for
children when data exist only for adults. And, she noted, children are part of the general
population, and referring  to them as a "subpopulation" carries the risk of trivializing the issue of
childhood risks, which effect all humans.  Dr. Farland said that children's risk assessment begins
by making an argument for a mode of action and then asking whether applying that mode of
action will be protective of the most sensitive individuals in the population. Unless there are data
to suggest that the mode of action applies to children or a cogent biological argument can be
made to suggest that it applies, the Guidelines assume it does not and the linear default is made.

Facilitated Discussion

       Abraham Tobia: One of the Guidelines' central points is the default assumption and the
movement from linear to  weight of evidence or the cogent argument. The Guidelines allow the
regulated community to generate information that addresses the cogent argument and move away
from the linear default. Dr. Tobia said that industry  has begun to look at the cogent argument
issue and to generate data by looking at the young without ignoring the older population. He said
there is a need for more pharmacokinetic and toxicokinetic data that address questions of
saturation and differential sensitivity between the young and old, and he urged that the
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Guidelines allow industry to be flexible in developing new studies based on emerging data
relevant to the cogent argument. The Guidelines should not be inflexible prerequisites, he said.

       Lauren Zeise: While linear defaults are conservative and protective, the current draft
Guidelines miss important exposures very early in life and very late in life when the difference in
risk can be as great as an order of magnitude. One major assumption implicit in the Guidelines
that may lead to miscalculation of risk is the homogeneity assumption, she said. The Guidelines
should incorporate a framework that allows adjustments for heterogeneities such as differences
across the population, polymorphisms, and other variability within species, timing of exposure,
and the impact of lifetime dose. The Guidelines'.assumption about lifetime average dose ignores
important information about timing of exposure, she said. Evaluation of epidemiological data
may reveal an environmental role in childhood cancers that now have no known cause. With
respect to the cogent biological rationale, it is critical to include data that make it possible to
calculate and integrate the effect of chronic background exposure, she said. The mode-of action
approach involves discussion of associations that support the hypothesis, she said. The
Guidelines should incorporate incentives, supported by Federal agencies, for a broader testing of
some hypotheses that are now employed in the mode-of-action approach.

        Daniel Krewski: Dr. Krewski said the new Guidelines' emphasis on mode of action was
a significant improvement, but noted that developing sufficient information on specific modes of
 action will be extremely difficult and emphasized that the Guidelines should encourage
 development of methods to acquire this information. Assumptions about lifetime average daily
 dose can lead to underestimations when early exposures are more important than later exposures
 because of children's differential susceptibility. He noted that there is a useful body of literature
 that describes tools which could be used to evaluate time-dependent exposures. He suggested that
 these methods could be modified to incorporate susceptibilities as a function of.time. Inter-
 individual variations and genetic susceptibilities may account for more than 10-fold differences

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in risk, and are not be adequately accounted for in current animal bioassays, Dr. Krewski said,
and he suggested an additional 10-fold assumption about risks to children. He urged that risk
assessments be based on data related to in utero and perinatal exposures to assure that the critical
period of exposure is identified. Some carcinogens act through mechanisms that could invoke
either linear or nonlinear models for risk assessment, Dr. Krewski said, and the Guidelines
should incorporate models that allow for consideration of both the linear and nonlinear
contributions, not one or the other. Dr. Krewski noted that pharmacokinetic studies can be a
powerful tool to  help identify specific susceptibilities in children. He also cautioned against ah
"across the board" confidence that an assumption of linearity offers the most conservative
evaluation of risk. Dr. Krewski said the Guidelines should also develop methods to take into
account the high risks that may be associated with human genetic factors alone or through their
interaction with varied environmental risk factors.

       Frederica Perera: Molecular epidemiology studies in humans make it possible to
examine the issue of differential susceptibilities between the fetus and the young child and the
variability among young populations. These studies take advantage  of biomarkers that can detect
molecular changes in samples of blood or other tissue.  This approach allows a better
understanding of specific exposures, early damage, and susceptibility. Studies involving
polycyclic aromatic hydrocarbons and other aromatics  such as pollution from coal burning,
traffic, and environmental tobacco smoke show that the fetus is at least 10 times more vulnerable
to damage than the mother. Other data from these studies show a differential susceptibility
among the children that is related to polymorphisms in the study population. Another study of
environmental tobacco smoke and preschool-age children also suggests that biomarkers can be
used to identify differential susceptibility related to ethnicity. Dr. Perera suggested that
biomarkers may  provide a means to identify specific susceptibilities and to gather sufficient data
to develop probabilistic models that could lead to improved defaults.
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Discussion

       George Lucier noted that recent studies, including some involving biomarkers, have
found 100-fold variations in vulnerability between individuals. Michael Thun observed that the
presentations and discussions at the Workshop have focused on two juxtaposed issues:

       On the one hand, a broad and "to the heart" issue of learning what causes, and what might
       prevent, cancer in children.
       On the other hand, the detailed mechanical considerations of risk assessment and
       regulation.

 In between, Dr. Thun noted, is a broad area of childhood cancer and its relationship with
 infectious agents and pharmacological agents that may act more subtly than DBS. This area may
 be beyond the province of the EPA, Dr. Thun said, and the Workshop should keep in mind that
 the EPA is not going to be able to eliminate childhood cancers. Dr. Landrigan observed that from
 70 to 80 percent of childhood cancers have unknown causes, but that it is clear that some are the
 result of exposure to manmade synthetic chemicals.  Human action is in part responsible for
 causing these cancers, Dr. Landrigan said, and human actions  such as the development of risk
 assessment guidelines can be used to prevent them. Retha Newbold suggested that the Workshop
 should not focus on childhood cancers to the exclusion of cancers that appear later in life but may
 be the result of exposures that occurred in childhood.

         Steven Galson asked Dr. Perera if sufficient data are available now to construct
 probabilistic modeling that can be used to develop new defaults. Dr. Perera replied that in her
 opinion enough data could now be gathered about the distribution of some genetic
 polymorphisms and nutritional factors, as well as known factors related to gender and ethnicity,
 to begin developing such models. Dr. Zeise added that some of these data could be integrated
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into a framework that helps describe individual differences and could be incorporated into risk
characterization.

       Chris Portier said there is no convincing argument that the linear default is conservative
as a rule and that there is confusion in the Guidelines as to what the confidence bound derived
from animal estimates really represents in terms of protection of population-based risk compared
with variants around an estimate. He said the question of choosing a point of departure from the
observable response region to the extrapolation region is also not clearly answered in the
Guidelines. Dr. Portier said the concept of cogent biological rationale might be appropriate in
adults but cannot now be applied as a reason for moving away from the linear default in
assessing childhood cancer risks because not enough is known about mechanisms acting in
childhood cancers. He also urged the Agency to look at data that help elucidate the effect of long-
term versus short-term exposures and carcinogenesis in children.

       Dr. Farland  said the Guidelines should help provide the best possible judgment about risk
to the population, and these judgments must then be applied to decision-making. It is important
to prevent even an extremely small risk, he said, and the  conservative nature of defaults makes
them an important tool in decision-making.  He also said  the Guidelines are open to the inclusion
of additional information and suggested that the Guidelines might incorporate language that
actively encourages the use of information such as data on biomarkers, epidemiologic
distributions, and ethnic factors. Dr. Portier noted that the draft Guidelines suggest that the
defaults would apply when there is neither adequate  data nor a cogent biological rationale. He
urged that the Agency be very careful to support with data any action regarding children. He said
that he did not believe sufficient information was available to make a cogent biological argument
for the factors associating exposure to  children's cancer.
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TOPIC 2: ENHANCED USE OF TEST DATA RELATED TO CHILDREN'S CANCER
RISK
RochelleTyf

       The currently-employed 2-generation reproductive toxicity test (OPPTS 870.3800)
monitors first-generation (F-l) animals exposed from the time they are gametes through
gestation, lactation, breeding, delivery, and weaning of second generation (F-2) animals. F-l and
F-2 generation animals are exposed "from womb to tomb" in this assay, Dr. Tyl said. She
described in detail the protocol and measured endpoints for evaluating effects on parental
animals and offspring. This study has the most potential for getting better information about
children's cancer risk than is now gathered. The study has the right exposure—spanning
development from gamete through adulthood—but gathers the wrong data for assessing
childhood cancer risks, Dr. Tyl said. She suggested that the study be extended to follow
development of F-2 animals beyond weaning of their offspring. This would allow detection of
long-latency cancers without the expense of carrying out separate chronic studies, she noted.

       The prenatal developmental toxicity test (OPPTS 870.3700) involves exposure from
 conception to birth. Because animals are necropsied at birth, this study captures only
 developmental effects of the prenatal exposure and can not detect postnatal effects, Dr. Tyl
 noted. Without major change in protocol, this test has very little value for assessing children's
 cancer, she said.

        The combined chronic/carcinogeniciry study (OPPTS 870.4300) involves exposure that
 begins at age 6-8 weeks and continues through 18 months for mice or 24 months for rats. The 90-
 day toxicity study (OPPTS 870.3100) involves exposure begun at 6-8 weeks and continued
 through 13 weeks. Immunotoxicity studies (OPPTS 870.7800)  begin exposure at 6-8 weeks and
 continue through 28 days. These studies make it possible to detect impairment of cells involved
 in immune response, and may be  incorporated into the combined chronic/carcinogenicity and 90-
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toxicity studies. Metabolism and pharrnaeokinetics studies (OPPTS 870.7485) begin a 7-day
exposure at age 6-8 weeks and are conducted only on male animals. All of these studies begin
exposure on young adult animals and can therefore not contribute to assessing risks of exposure
during development or childhood, Dr. Tyl observed.

       In conclusion Dr. Tyl said that the 2-generation studies, which involve exposure
beginning at implantation, hold the most promise for gathering information specific to childhood
risk. Following up F-2 generation animals through a chronic study would result in a study that
incorporates the appropriate exposure with long duration study. This would allow detection not
only of childhood cancers but also adult cancers initiated by childhood exposure.

Facilitated Discussion

       Mark Miller: A systematic review of data gathered in other animal studies may reveal
timing and organ-specific information on mode of action that can be used to compare adults and
children. The single-exposure carcinogenesis data base may be one area that might be fruitfully
explored, Dr. Miller said. He  suggested that reviewing existing research results to sort species by
chemical may help identify which species are best suited as models for specific chemicals. The
developing area of research into immune system effects should be integrated into testing for
cancer risk in children, he said.  Precancerous conditions such as myeloplastic syndrome, which
progresses to acute myeloid leukemia, are frequently associated with specific  genetic markers
and could reveal some associations between exposures and childhood cancer,  Dr. Miller
suggested.
       Paul Foster: Current reproductive and developmental studies involving prenatal and
juvenile exposure were not designed for cancer endpoints. With some modification these tests
might reveal early indicators of change related to cancer, but as they are now designed these tests

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reveal the most relevant exposures but the least relevant endpoints for cancer risk, Dr. Foster
said. Among the current studies, data gathered in multigenerational studies have the most
potential for revealing childhood cancer risk, but the selective culling of animals in these studies
must be modified to include more, and more representative, animals per generation, he said.
Currently available "non-standard" data that may be collected include responses during specific
developmental windows of opportunity and hormone-like activity of possible carcinogens. Dr.
Foster also suggested that developmental stages of test animals compared with humans must be
considered. For example, he noted, early  brain development that occurs prenatally in humans
takes place postnatally in rodents. Dr, Foster said that studies using transgenic rodents may
increase the sensitivity of the tests for specific cancers, but he cautioned that results obtained
from the study of increasingly sensitive rodents may have decreasing relevance to humans. There
is a huge opportunity to use the emerging knowledge of human and animal genomics to find
common mechanistic pathways for development of cancers, he said.

        Dr. Foster said current prenatal developmental toxicity  studies look at inappropriate
 endpoints and are of no practical use in studying children's cancers, but that current
 multigenerational studies could be modified to produce data relevant to childhood cancers.
 Overcoming the limitations of current studies would require modifications such as determining
 correct dose levels and increasing the number of animals studied from each litter, but extensive
 modifications run the risk of making the studies too large and complex to be conducted
 effectively, he said.
 General Discussion
        Dr. Goldman noted that the discussions of modifying current tests involve looking more
  and more carefully at an increasingly homogeneous population of animals, and she contrasted
  that with opinions voiced earlier in the Workshop suggesting that existing studies are too
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narrowly defined to capture the variability in exposure and susceptibility in children. One aspect
that needs to be more fully explored, she said, is the uniquely human characteristic of not breast-
feeding infants. Dr. Tyl noted that even the highly inbred rodent strains used in laboratory studies
do exhibit some variability, but agreed that it is small. It would not be possible, Dr. Tyl said, to
design animals studies  that reflect the variabilities of the human population. George Lambert
agreed that the world of animal science does not reflect the conditions encountered by human
children. He suggested that this disparity argues for focusing on mechanism of action in
children's cancer studies. George Lucier suggested that the limited variability encountered in
animal studies could be examined more thoroughly to detect early markers that might be related
to variation. He also noted that a common mode of action, such as a receptor-mediated toxicant,
may produce different responses depending on the timing of exposure or the organ system
involved. Lucy Anderson said that studies that involve total  life exposure involve influences
from conception through adulthood that may be additive, synergistic, or cancel out. Identifying
these effects would require different exposure patterns (preconception only, during gestation,
neonatal, and adult) to  assure that critical effects are detected. She also agreed with earlier
comments that studies  involving unculled litters studies could provide more information about
variability. Joseph DeGeorge emphasized the importance of timing exposures to coincide with
developmental stages, and noted that current rodent studies involve extrapolations from one
developmental stage to another. Extending these extrapolations still further, from rodents to
humans, must be done  carefully, he noted. He suggested that more fully examining modes of
action can avoid some  of the uncertainties of extrapolation.
       William Farland noted that the regulatory toxicology tests are a very sensitive system that
is used to make judgments that rodent responses are relevant to humans for hazard identification
and that what is seen at high doses is relevant to low doses. He also said that animal studies are
beginning to identify biomarkers that can also be examined in human populations. He suggested
that information gathered about human biomarkers might be incorporated into animal models
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through bioengineering. Dr. Landrigan noted that exposures in the toxicology testing mentioned
by Dr. Farland began when the animal had already reached adolescence and therefore is missing
important endpoints. He suggested that more meaningful data might result from tests in which
exposure began in utero and necropsy did not take place until the animal died naturally. Dr.
Farland responded that background effects of natural aging would complicate this type of
analysis, but agreed that tests in which exposure begins in adolescence miss the biological effects
of early exposure. David Wallinga questioned the usefulness of standard toxicity tests using
inbred animals to reflect the wide variability in humans. Moreover, he noted, the current
Guidelines implicitly assume that all humans are the same because there is no mention of
variabilities in susceptibility to carcinogens.

       Les Robison suggested that the development of intermediate lesions might be a useful
precancerous marker for some childhood cancers. He also expressed concern about the reliability
of data derived from animal models to parallel the mechanisms and outcomes of human
childhood cancers.

       Chris Portier noted that the mode of action approach in the Guidelines likely
accommodates most if not all of the concerns he had raised in earlier discussion about the
strength of available information in forming a cogent biological rationale. He supported the idea
of using the multigenerational study as a framework for developing a children's cancer bioassay,
but observed that the selection of some animals over others for study  in each litter could result in
seriously overestimating or underestimating risk. The selection, he said, might be an unintended
result of culling, but also might be a result of the chemical itself. He also noted that studies
involving enough non-littermates to acquire meaningful data might require prohibitively large
numbers of animals. George Lambert noted that studies focusing on mechanism of action would
yield information relevant to risk for populations with different susceptibilities and inter-
 individual variations.
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       Chris Wilkinson noted that the discussion about problems posed by human heterogeneity
and the homogeneity of animal models overlooks the broader question of whether the rodent
model is adequate to assess risks in children in view of the fact that a newborn rat is essentially
equivalent to a human fetus. He suggested that developing new studies might be more productive
than modifying protocols of existing models because the huge numbers of animals needed for
study would pose a serious problem. He asked that the Workshop concentrate less on
environmental chemicals and consider ways to assess the risk of Pharmaceuticals, food additives,
or over-the-counter drugs, which may have substantial in utero impact. He said that
understanding modes or mechanisms of action makes it possible to plausibly extrapolate from
adult risk to children's risk.

       David Goldsmith said the Workshop should be cautious in relying on developments that
may or may not derive from fuller knowledge of the human genome. He also suggested that
epidemiologic data can support dose-response data gathered in laboratory studies and should be
integrated more fully into the risk assessment process.

       John Doe said that testing homogenous animal models at maximum dose can lead to false
positive associations, which is protective of public health. He also said it was important to
reiterate the point that the biggest difference between adult risk and children's risk is due to
exposure and not to hazard.

       David Byrd said that there is a rich literature addressing the issue of the sensitivity of
false positive and false negative aspects of bioassays. Unfortunately, he said, the chemicals
represented in that data are not representative of the universe of environmental chemicals. He
also noted that variability represented in the animal  species used in current bioassays is much
greater than the variability within the human population.
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TOPIC 3: FUTURE DIRECTIONS FOR TOXICOLOGY TESTING TO ADDRESS
CHILDREN'S CANCER RISK
Retha Newbold

       Dr. Newbold focused on research into the effects of DBS as an example of the cancer risk
associated with prenatal exposure to estrogenic chemicals. The developing organism is extremely
sensitive to estrogenic compounds, particularly during specific stages of development, and the
effects of exposure may not appear until much later in life. DBS was prescribed as safe and
effective to reduce risk of miscarriage, but now is known to have resulted in a low incidence of
vaginal cancer and a high incidence of male and female reproductive tract dysfunction on
offspring. Research into the effects of DBS demonstrated that a carcinogen can act across the
placenta, that its activity is different from other carcinogens, and that its effects in humans can be
accurately modeled in animals. Prenatal exposure of animal models results in developmental
effects in both male and female mice that closely parallel the effects found in humans, thereby
validating the experimental model as a means of predicting human disease. Neonatal studies, in
which exposure occurs during the first week of life, demonstrate that exposure to estrogenic
compounds during the period of uterine development—prenatal in humans and postnatal in
mice—is associated with uterine cancer. These studies confirm the critical role of timing of
exposure during developmental stages. To determine if the changes due to estrogenic exposure
could be transmitted to subsequent generation, researchers bred females exposed prenatally or
neonatally to control males and evaluated female F-2 offspring at maturity. Among the F-2
 females, reproductive fertility was not effected, but the animals showed an increase in incidence
 of reproductive tract tumors. Additional research is underway to determine the mechanisms
 involved in these generational effects. Research advances developed through these studies of
 estrogenic compounds may be applied to the development of more sensitive animal models of
 other carcinogens.
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Facilitated Discussion

       George Lambert: Risks to children from possible carcinogens can be studied in much
the same way as drugs are evaluated through pharmacokinetic and pharmacodynamic (PK/PD)
models, mechanisms of action, absorption, distribution, metabolism, and effect. These studies ,
can elucidate some of the differential susceptibilities between children and adults as well as those
due to interindividual variability. PK/PD studies are well suited to identifying differences
between the fetus and child or between child and adult. In humans, cells and tissues from
children and adults can be used to identify biomarkers that may be predictive. Dr. Lambert noted
that drugs, which are developed for use in a tightly defined population, are subjected to more
stringent examination than chemicals to which the whole population made be exposed through
the environment. He suggested that post-marketing surveillance of chemicals would reveal
patterns of distribution, exposure, accumulated body burdens, and adverse effects.
       David Wallinga: Dr. Wallinga noted that the Workshop has been struggling to deal with
two different questions: what information is available and what information do we really need.
He said that the information available is limited and the data are poor. For example, he noted,
only a small percentage of the 80,000 registered industrial chemicals have been studied in even
limited detail for toxicity or carcinogenicity. He cited the National Research Council's 1993
observation that current testing protocols do not adequately address the toxicity and metabolism
of pesticides in neonate or adolescent animals. NRC also determined that infants and children are
more susceptible to risk than adults to the toxic effects of chemicals, even though chemical-
specific data may not be available. He noted the reasons for increased susceptibility and said that
the Guidelines should incorporate strong defaults assumptions and establish high hurdles to
abandoning those defaults. He said that the "cogent biological rationale" mentioned in the
Guidelines is not well defined and that the default assumptions in the Guidelines should be
closely examined to assure that they are sufficiently health-protective. For example, he said, the
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Guidelines do not require data bearing on variability, interactions, or pharmacokinetic data in
developing animals. Dr. Wallinga recommended that future testing should:

       Extend developmental toxicity tests beyond birth to account for latency.
       Assess cancer risk from pre-conceptual exposure.
       Look at effects of short-term carcinogen exposure during developmental windows.
•      Require pharmacokinetics in immature animals.
       Build developmental windows of vulnerability into the testing paradigm.
•      Validate and test for endocrine disruption.
•      Do semiquantitative assessments of cumulative risk.

       Dr. Wallinga noted in closing that child-protective changes to the Guidelines can't wait,
as the Guidelines have been applied since 1996 to at least 45 pesticides and will, by the end of
FY 2001, have been used to establish new or revised IRIS assessments for at least 64 other
chemicals.

       Joseph DeGeorge: Dr. DeGeorge said that it is important to  consider the appropriateness
 of the juvenile animal model before it is used to make predictions for children's risk assessment.
 For example, he noted, if a toxicant needs activation by a metabolic process that the animal
 model does not contain, the risk to children will be underestimated or missed. He said that if an
 animal model is determined to be appropriate, the model must address exposure during the
 proper organ developmental stage. The timing and method of exposure must be carefully selected
 to assure that the effects of the chemical are isolated from confounding factors. For example, he
 observed, exposure through lactation also involves exposure to metabolites. Dr. DeGeorge
 recommended that more biomarkers be incorporated into the Guidelines, and that new
                                             34

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31, 2000
biomarkers be added when they have been validated. He said that improving dose-response
assessment will be one of the most difficult challenges to the Guidelines because of the
complexity of exposure in humans. For example, he noted, the effective dose of the commonly
used nutritional supplement St. John's wort is reduce by 50 percent in persons taking protease
inhibitors, and grapefruit juice can increase the effective exposure to other Pharmaceuticals.

Discussion
       Rochelle Tyl noted that much of the existing data on carcinogenicity have been based on
testing at the maximum tolerated dose. This means, as a practical matter, that the test animal's
metabolic capacity has been exceeded and no longer represents the effects in normal animals.
This may lead to quantitative differences in the measured outcomes and lead to inaccurate
conclusions about tested chemicals. John Doe said there is a practical problem associated with
test methods that rely on the induction of tumors as an endpoint. This approach would involve
huge experiments to assess the effect of in utero, early postnatal, postnatal through life, and
conventional dosing protocols. This complexity could be avoided through concentration on
identifying precursor events and other markers. The dilemma this poses, he noted, is that these
markers will not provide information that is as definitive as tumor initiation. Penelope Fenner-
Crisp noted that much of the revised and expanded testing being discussed would have to be
imposed on industries, a procedure that would require regulatory authority that does not now
exist. David Wallinga said that one of the purposes of defaults in risk assessment is to drive
research, and they should be used to drive research that generates data specific to children's risk.
George Lambert noted that the development of many FDA regulations has been driven by
Pharmaceuticals' risks to children, and suggested that the same concern might be brought to bear
on children's risks for cancer. Angelina Duggan noted that agricultural industries are beginning
to generate epidemiologic data that can be used to evaluate family exposures to chemicals that
are handled only by male farm workers. William Farland pointed out that the existing default

                                            35

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
structure accounts for human variability through the implicit assumption that humans are at least
as sensitive as the most sensitive test animals.

TOPIC 4: EPIDEMIOLOGIC/MOLECULAR EPIDEMIOLOGY INFORMATION TO
ADDRESS CHILDREN'S CANCER RISK
Leslie Robison

       Epidemiologic research is crucial to identifying risk and working to prevent childhood
cancer. These cancers are rare and unique, which makes epidemiologic study difficult. Acquiring
adequate etiologic data for childhood cancer will require a national effort to create a network for
research that would include:

       A national registry of children with cancer for identifying environmental and other causes
       of childhood cancer.
       Building upon the unique national clinical trials system for treating children with cancer.
       Identifying children at the time of diagnosis, allowing collection of tissue specimens.
       Coordination of efforts with population-based cancer registries.
       Support and facilitation of scientific studies of the highest merit by qualified investigators
       to study causes of cancer in children.

       The effort must be national in scope because of the differences between children's
 cancers  and those in adults and the relatively small numbers of children with any specific
 diagnosis. Only a national effort would be able to compile enough data about the 8,700 cases of
 childhood cancer diagnosed each year to make meaningful evaluations of specific cancer types. A
 national network would make it possible to identify causes and to more fully understand known
 risks factors, Dr. Robison said, and it would also lead to advances in molecular characterization
 of tumors, exposure assessment methodology, and understanding genetic susceptibility. Among
                                            36

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
the improved methodologies and technologies that might be developed through a national effort
are:
•      GIS technologies for hypothesis generation and correlation.
•      Sophisticated categorization of occupational categories relevant to specific exposures.
       Exposure assessment through the ability to detect minute quantities of substances in
       biological fluids and in the environment.
•      Identification of biological markers of exposure and susceptibility.
       Identification of potential genetic susceptibility factors.

       A national effort would overcome the limitations of previous childhood cancer causation
studies and have the secondary benefit of making possible a study of patterns of care and
enhancing  surveillance capabilities.

       The national network initiative for children's cancers could use as its foundation existing
clinical trial cooperative groups such as the Children's Cancer Group and the Pediatric Oncology
Group, which represent more than 200 institutions throughout North America. These existing
groups, which will combine as the Children's Oncology group, have developed extensive
epidemiologic data on a variety of childhood cancer, but have not yet developed substantial
information on the etiologic of children's cancers. A framework for the structure and registration
protocol, as well as a projected development time line have been developed. When established,
the national network will make it possible to track the progression of pediatric cancer survivors
and examine the effects of medical exposures to therapeutic radiation, intermediate markers and
biomarkers of effect and progression, and cancer outcome.
                                            37

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
Facilitated Discussion

       Michael Thun: The cancer control community is interested in what epidemiologic
approaches will have the biggest effect in identifying the causes of childhood cancer and
preventing childhood cancer. The small relative numbers of childhood cancers severely limits
possibilities for epidemiologic study. For example, although there is a spike in the incidence of
acute lymphoblastic leukemia between ages 2 and 4, the average number of cases is fewer than
85 per million. A cohort of 1 million children enrolled at birth and followed until age 20 would
experience the following cancers:

•      Leukemia
       Acute Lymphoblastic        596
       Acute Myeloid             154
•      Lymphoma
       Hodgkins                  240
       Non-Hodgkins             210
       CNS - Astrocytoma        280

       Thus, even a huge cohort study would not produce numbers large enough to provide
meaningful study of the incidence of the most common childhood cancers. An epidemiologic
study looking at genetic polymorphisms through relation of disease to a gene would require
between 2,000 and 3,000 cases to achieve enough statistical power to look at gene/environment
interaction.
       Dr. Thun noted that understand the causes and means of preventing childhood cancers has
 been a real, pervasive, and persistent concern in the public health community and among parents.
 It is a problem that needs to be addressed across agencies, and should not be considered
 separately within EPA or the National Cancer Institute, he observed. He recommended that
                                           38

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
federal agencies jointly fund a data resource that could make headway against childhood cancers,
which, although rare, cause enormous grief.

       Lucy Anderson: Animal models should be developed for studying factors such as
susceptibility and stage specificity, which are not typically covered in current animal bioassays,
Dr. Anderson said. In addition, historical literature should be investigated to gather data on stage
specificity, susceptibility factors, and other issues that are meaningful to childhood studies. New
studies to test putative associations, hypotheses, and the validity of biomarkers are needed. These
could be well-designed modifications of current studies or new protocols involving transgenics,
but they will only be carried out with government financial support, she said. The Guidelines
should incorporate studies that examine the role of fathers in children's risks,  an issue has been
overlooked in the regulatory context even though epidemiological and animal evidence suggests
an important role of paternal exposure, she said. There is reason to believe that a qualitatively
novel mechanism exists to contribute to preconceptional carcinogenesis related to gene
expression, she said. These tests could be designed to detect the role of paternal exposures
through carcinogens in pesticides, drinking water contaminants, and tobacco smoke.

       Peggy Reynolds: Evidence of an association between increased incidence of lung cancer
and early initiation of smoking may suggest evidence of mechanisms of early exposure as a cause
of later life cancers. A multicenter study of lung cancer in nonsmoking women,  which investigated
the role of environmental tobacco smoke (ETS) in cancer among nonsmokers, found no increased
risk of childhood cancers associated with childhood ETS exposures, but found that for adult
cancers, women with childhood exposures had nearly twice  the risk associations of women with
adult ETS exposures. This finding may illustrate the issue of "shelf life" as a factor in later life
development of cancers resulting from early life exposure, Dr. Reynolds noted.
                                            39

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
       Chris Portier: Establishing a cancer registry would be usefUl in understanding the
etiology of childhood cancer and, even if it is not environmentally related, will help us to
understand better the environmental issues associated with childhood cancer. Developing and
following large enough cohort studies of biomarkers will be very difficult. The difficulties are
more pronounced for cancers that occur in adults as the result of in utero, postnatal, or childhood
exposures.
 General Discussion

        Daniel Krewski commented on the value of nationwide registries to examine childhood
 cancers, and discussed the types of information and biological specimens that are acquired in
 Canada's cancer registry. Adult cancer registries might serve as models for childhood cancer
 registries, which would not only be valuable in current studies but also represent an incalculable
 resource for future research. Leslie Robison noted that the highest single age-specific rate for
 childhood cancer is in the first year of life.

        Some pediatric cancers have genetic origins, Dr. Robison said, but most are initiated in
 utero. He added that the evidence for a paternal role in children's cancer is driven by data on
 occupation, although some animal models show an association between preconceptional radiation
 exposure and cancer in offspring. Dr. Robison said a national birth cohort study would not be
 likely to make a meaningful contribution to the study of children's cancers but could reveal
 patterns of association between childhood exposure and adult cancers. Moreover, he said, a birth
 cohort would be invaluable as a means of tracking exposures.

        William Farland and Philip Landrigan described the efforts of an interagency task force,
 chaired by  the Secretary of HHS, the Surgeon General, and the Administrator of the EPA, to
 initiate a nationwide birth cohort that would register at least 100,000 ethnically and racially
                                              40

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31, 2000
diverse children as early as possible in pregnancy. Statistical information and biological samples
would be obtained from the parents as well as the child, who would be followed with
standardized examination protocols to age 18. Many details remain to be worked out, Dr.
Landrigan said, but the effort has begun and has enormous promise as a means of increasing
understanding of the etiology of childhood diseases other than cancer. Dr. Robison noted that
although the birth cohort could not directly address childhood cancer as an outcome it would
provide data on exposure assessment that could have incalculable value to the ability to do cancer
related research in the future. Chris Portier said that a cancer registry would have more value to
childhood cancers than a birth cohort. Philip Landrigan repeated his  earlier comment that it is
inarguable that children are more heavily exposed to carcinogens than are adults, that developing
organ systems are more vulnerable than fully formed systems, and that children have more years
of future life in which to develop cancers than do adults.

       Joel Bender observed that the Workshop and similar discussions may not have been able
to reduce uncertainty about the Guidelines but have been successful  in articulating a national
agenda to fill data gaps. A question that needs to be answered, he said, is whether the scientific
community is comfortable  with the Guidelines until those gaps are filled. Lynn Goldman
expressed confidence that discussions would result in modifications  to the Guidelines that
appropriately respond to concerns about pediatric cancer. David Goldsmith asked that serious
consideration be given, when establishing a birth cohort, to the disproportionate burden of severe
environmental and health problems borne by minority communities. He suggested that minority
children be oversampled as a method of assuring that their risks be fully incorporated into the
overall consideration of public health.
                                            41

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
WORKSHOP SUMMARY
George Lucier

       Dr. Lucier repeated the basic charge that the Workshop should serve as an opportunity to

help assure that the Guidelines for Cancer Risk Assessment accommodate as much information

as possible to adequately identify and assess risks to children. He noted the major themes that

emerged from the Workshop presentations and discussions:


       Children should not be considered a special population; rather, childhood should be
       considered a stage of development characterized by increased sensitivity to chemical
       exposure.

•      Evaluating margins of exposure requires better information on external exposures from
       environmental sources such as air, food, and drinking water. Data on internal exposures,
       as measured in blood or urine levels, is often not available for childhood exposures.
       Pharmacokinetic and pharmacodynamic models can help elucidate childhood exposures.
       All of this information should be considered with respect to exposure during critical
       "windows" of organ  development and cell differentiation.

       Important sensitivity factors include developmental stage and genetic predisposition.
       Much information that will emerge from refined test protocols, human genomics studies,
       and other resources will bear on these issues, and organizing this new information into a
       coherent picture of childhood cancer will be a challenging task. Other important
       sensitivity  issues relate to nutrition, "shelf life" (i.e., when exposure occurs during
       childhood, there is a long latency period available for cancers to develop), and
       interactions between multiple environmental, physiological, and genetic factors.

       Mode of action (MOA) assessments should evaluate conditions in which different modes
       lead to different risks (children compared with adults, for example) as well as when the
       same mode leads to different risks. Genotoxic and nongenotoxic are oversimplified
       distinctions when considering mode of action in the context of deciding whether to use
       linear or nonlinear assumptions about risk. Background exposures must be taken into
       account when considering MO A, as multiple factors with the same mode of action could
       result in a cumulative risk.
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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31, 2000
•      Dose-response studies are difficult but important, and should take into account
       background exposures, variability, dose selection and timing, and the applicability of
       surrogate markers and early indicators.

       Uncertainty factors include the realization that using defaults to account for variability is
       more difficult than using them to account for species differences. The 10-fold safety
       factors now used to account for species differences are public-health-protective, but may
       not accurately reflect interindividual differences or differential genetic susceptibility;
       therefore additional safety margins may be needed. Additional factors may be needed to
       adequately assess children's exposure, and linear assumptions may not always be the
       most conservative.

•      Guidelines should not be overly prescriptive and should be able to stand the test of time.
       Guidelines that include highly detailed descriptions of their application may prove to be
       too inflexible to allow new approaches and new models to be used as they become
       available.

•      Regarding a cogent biological rationale that justifies an assumption other than the
       guideline default: for children, the bar should be high enough to be public-health-
       protective, and the models used will require rigorous peer review.


Discussion


       Rochelle Tyl asked what could be expected as a result of the Workshop. Dr. Lucier

replied that the Workshop's purpose was to identify what information needs to be captured by the

Guidelines in order to more fully understand children's risks. This information, he said, would be
used to revise the current draft Guidelines.  William Farland noted that the Workshop discussion

provided valuable insight into the need for  data collection and generated ideas about revisions to
epidemiologic studies and laboratory testing protocols that may be incorporated into testing

Guidelines to assure that they fully address risks unique to children. He also noted that the

discussions of improved testing protocols would be valuable in improving other Agency
guidelines. David Wallinga urged that the Guidelines incorporate an explicit mention of
principles particular to dose-response or mode of action, such as a statement that, in the absence
of data to the contrary, mode of action for children is presumed to be different than for adults. A

                                            43

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
similar principle could be framed for children's exposures, Dr. Wallinga said. Dr. Lucier
suggested that it would be necessary to develop credible models in order to obtain sufficient data
to fill the gaps in current understanding of both susceptibility and exposure.

       Dr. Lambert noted that, for many children's cancers, susceptibility may be far more
significant than exposure. Michael Firestone urged that the effort to improve testing
methodologies be continued beyond the revision to the Guidelines and that the issues of windows
of susceptibility and differential exposure be built into the Guideline discussions of cogent
biological rationale. Rochelle Tyl suggested that the Guidelines incorporate a specific definition
of cogent biological rationale. Each researchers has their own perception of what the term means,
she said, but the Guidelines would benefit from a definition that articulated details such as types
of studies and timing of exposures that would satisfy the requirements of producing a cogent
rationale. Lynn Goldman responded that the Guidelines should be less specific, not more
detailed. Spelling out specifically how the Guidelines are to be applied today will make it more
difficult to apply them more effectively in the future, she said. Abraham Tobia replied that the
Guidelines do need some detailed and specific guidance to the research community, perhaps as
appendices or illustrative examples. Such examples, he said, would provide insight into the
thinking that underlies the Guidelines and therefore provide valuable direction to researchers,
particularly in regulated industry. Dr. Farland noted that the Workshop discussions had generated
a much clearer perception of what information is needed to clarify issues such as cogent
biological rationale, and suggested that the Guidelines might benefit from inclusion of a case
study or other example that more clearly articulates the concept of cogent biological rationale.

        John Doe noted that new testing regimes need to be developed in response to the need for
 specific types of new information, and said that these new testing protocols should replace older
 study designs rather than being presented as add-ons to an already-burdened testing structure. Dr.
 Tobia said that any new studies must be rigorously tested and validated before they are
                                             44

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Summary of EPA Workshop on Information Needs to Address Children's Cancer Risk
Final Report, October 31,2000
incorporated into the Guidelines. He noted that the add-ons to multigenerational studies
discussed earlier in the Workshop could easily lead to a protocol that requires far higher numbers
of animals and round-the-clock attention by technicians and would make testing too complex and
prohibitively expensive. Dr. Goldman and Retha Newbold both cautioned that animal welfare
issues could become an important consideration if testing protocols become more complex, and
suggested that the Agency pursue development of studies that reduce the need for animal models.

       Dr. Landrigan urged that children's risk should be an integral part of the overall cancer
risk Guidelines, not an afterthought. Dr. Farland said that he expected the final Guidelines to
include an explicit mention of children's risks. He noted that the purpose of the Guidelines was
protection of public health and that protection of children as among the most vulnerable is an
integral component of that goal. This point will be clearly made in the Guidelines, he said.

       Dr. Landrigan and Dr. Goldman thanked the Workshop participants and observers for
their efforts  and contributions. Dr. Farland expressed EPA's gratitude to the Workshop chair and
cosponsor and closed the Workshop by saying that all the participants could leave knowing that
they had contributed to progress.
                                            45

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      APPENDIX A




WORKSHOP PARTICIPANTS

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&EPA
United States
Environmental Protection Agency
Office of Research and Development
National Institute of
Environmental Health
Sciences
    Workshop on Information
    Needs  to Address
    Children's Cancer Risk
    Holiday Inn Arlington at Ballston
    Arlington, VA
    March 30-31, 2000
    Final  List of  Invited Participants
     Lucy Anderson
     Chief, Perinatal Carcinogenesis Section
     Laboratory of Comparative Carcinogenesis
     Frederick Cancer Research &
     Development Center
     National Cancer Institute
     7th Street EXT.
     Building 538 - Room 205-B
     Frederick, MD 21702
     301-846-5600
     E-mail: andersol@ncifcrf.gov

     Joseph DeGeorge
     Center for Drug Evaluation & Research
     Food and Drug Administration
     Department of Health & Human Services
     1451 Rockville Pike
     HFD 024 WOC II - Room 6067
     Rockville, MD 20852
     301-594-5476
     Fax: 301-594-5147
     E-mail: degeorge@cder.fda.gov

     William Farland
     Director
     National Center for Environmental Assessment
     Office of Research & Development
     U.S. Environmental Protection Agency
     Ariel Rios Building
     1200 Pennslyvania Avenue, NW(8601 D)
     Washington, DC 20460
     202-564-3322
     Fax: 202-565-0090
     E-mail: farland.william@epa.gov

     CLj) Printed on Recycled Paper
                            Penelope Fenner-Crisp
                            Office of Pesticide Programs
                            Office of Prevention, Pesticides &
                            Toxic Substances
                            U.S. Environmental Protection Agency
                            Ariel Rios Building
                            1200 Pennslyvania Avenue, NW(7501 C)
                            Washington, DC 20460
                            703-605-0654
                            E-mail: fenner-crisp.penelope@epa.gov

                            Michael Firestone
                            Office of Children's Health Protection
                            U.S. Environmental Protection Agency
                            Ariel Rios Building
                            1200 Pennsylvania Avenue, NW(1107)
                            Washington, DC 20460
                            202-260-7778
                            Fax: 202-260-4103
                            E-mail: firestone.michael@epa.gov

                            Paul Foster
                            Chemical Industry Institute of Toxicology
                            6 Davis Drive
                            Research Triangle Park, NC 27709
                            919-558-1274
                            Fax: 919-558-1300
                            E-mail: foster@ciit.org
                                        A-3

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Steven Galson
Office of Science Coordination & Policy
Office of Prevention, Pesticides &
Toxic Substances
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennslyvania Avenue, NW(7201)
Washington, DC 20460
202-260-6900
Fax: 202-401-0849
E-mail: galson.steve@epa.gov

Lynn Goldman
School of Public Health
Johns Hopkins University
624 North Broadway - Room 441
Baltimore, MD  21205
410-614-9301
Fax:410-659-2699
E-mail: lgoldman@jhsph.edu

Daniel Krewski
Professor
Department of Medicine and
Department of Epidemiology &
Community Medicine
University of Ottawa
451 Smyth  Road - Room 3229C
Ottawa. ON K1H8M5
CANADA
613-562-5800, Ext.: 8261
Fax:613-562-5465
E-mail: dkrewski@uottawa.ca

George Lambert
Environmental & Occupational
Health Sciences Institute
681 Frelinghuysen Road - #406
Piscataway, NJ 08854
732-445-0174
Fax:732-445-0119
E-mail: glambert@umdnj.edu

Philip Landrigan
Department of Community &
Preventive Medicine
Mount Sinai School of Medicine
 101st Street-#10(BSB)
Between Fifth & Madison Avenues
 New York,  NY 10029
212-241-4804
 Fax: 212-996-0407
 E-mail: phil.landrigan@niehs.nih.gov
George Lucier
National Institute of Environmental
Health Sciences
National Institutes of Health
111 T.W. Alexander Drive
Building 101 - Room A330
Research Triangle Park, NC 27709
919-541-3802
Fax: 919-541-3647
E-mail: lucier@niehs.nih.gov

Mark Miller
Office of Environmental Health
Hazard Assessment
California Environmental Protection Agency
1515 Clay Street - 16th Floor
Oakland, CA 94612
510-622-3159
Fax: 510-622-3210
E-mail: mmiller@oehha.ca.gov

Retha Newbold
National Institute of Environmental
Health Sciences
National Institutes of Health
111 T.W. Alexander Drive
Building 101 - Room 344
Research Triangle Park, NC 27709
919-541-0738
Fax:919-541-4634
E-mail: newbold1@niehs.nih.gov

Frederica Perera
Columbia University
40 East 94th Street - #30A
New York, NY  10128
212-304-7280
Fax: 212-544-1943
E-mail: fpp1@columbia.edu

Chris Portier
National Institute  of Environmental
Health Sciences
National Institutes of Health
111 T.W. Alexander Drive
Building 101 - Room A344
Research Triangle Park, NC 27709
919-541-4999
Fax: 919-541-1479
E-mail: portier@niehs.nih.gov
                                            A-4

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Leslie Robison
University of Minnesota
425 East River Road
Cancer Center Research Building - Room 554
Minneapolis, MN 55455
612-626-2902
Fax: 612-626-4842
E-mail: robison@epi.umn.edu

Michael Thun
Vice President, Epidemiology &
Surveillance Research
American Cancer Society
1599 Clifton Road, NE
Atlanta, GA 30329
404-329-5747
Fax: 404-327-6450
E-mail: mthun@cancer.org

Abraham Tobia
Manager, Toxicology
Toxicology Group
Aventis CropScience
2 T.W. Alexander Drive
Research Triangle Park, NC 27709
919-549-2213
Fax: 919-549-2925
E-mail: abe.tobia@aventis.com
Rochelle Tyl
Research Triangle Institute
3040 Cornwallis Road (HLB-245)
Rsearch Triangle Park, NC 27709
919-541-5972
Fax: 919-541-5956
E-mail: rwt@rti.org

David Wallinga
Senior Scientist
Natural Resources Defense Council
1200 New York Avenue, NW - Suite 400
Washington, DC  20005
202-289-2376
Fax: 202-289-1060
E-mail: dwallinga@nrdc.org

Lauren Zeise
Chief, Reproductive & Cancer
Hazard Assessment
Office of Environmental Health
Hazard Assessment
California Environmental Protection Agency
1515 Clay Street-16th floor
Oakland, CA 94612
510-622-319,5
Fax:510-622-3211
E-mail: lzeise@oehha.ca.gov
                                           A-5

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   APPENDIX B




LIST OF OBSERVERS

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SrEPA
United States
Environmental Protection Agency ,
Office of Research and Development
National Institute of
Environmental Health
Sciences
    Workshop on Information
    Needs  to Address
    Children's Cancer Risk
    Holiday  Inn Arlington at Ballston
    Arlington, VA
    March 30-31,2000

    Final List of Observers
    Daniel Axelrad
    Analyst
    Office of Policy
    U.S. Environmental Protection Agency
    Ariel Rios Building
    1200 Pennslyvania Avenue, NW(2174)
    Washington, DC 20460
    202-260-9363
    Fax: 202-260-0512
    E-mail: axelrad.daniel@epa.gov

    Karl Baetcke
    Senior Scientist
    Office of Pesticides Programs
    U.S. Environmental Protection Agency
    Ariel Rios Building
    1200 Pennsylvania Avenue, NW (7509C)
    Washington, DC 20460
    703-305-7397
    Fax:703-605-0646
    E-mail: baetcke.karl@epa.gov

    Donald Barnes
    Director, Science Advisory Board
    U.S. Environmental Protection Agency
    Ariel Rios Building
    1200 Pennslyvania Avenue, NW (1400 A)
    Washington, DC 20460
    202-564-4533
    Fax: 202-501-0323
    E-mail: barnes.don@epa.gov
                            Ted Barrera
                            President
                            Barrera Associates, Inc.
                            733 15th Street, NW- Suite 1120
                            Washington, DC 20005
                            202-638-6631
                            Fax: 202-638-4063

                            Lisa Barrera
                            Senior Vice President
                            Barrera Associates, Inc.
                            733 15th Street, NW- Suite 1120
                            Washington, DC 20005
                            202-638-6631
                            Fax: 202-638-4063

                            Joel Bender
                            4601 Ginger Trail
                            Toldeo, OH  43623
                            419-472-8390

                            Marilyn Brower
                            Office of Research & Development
                            National Center for Environmental Assessment
                            U.S. Environmental Protection Agency
                            Ariel Rios Building
                            1200 Pennsylvania Avenue, NW(8601 D)
                            Washington, DC 20460
                            202-564-3363
                            Fax: 202-565-0062
                            E-mail: brower.marilyn@epa.gov
       i Printed on Recycled Paper
                                       B-3

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Daniel Byrd
President
CTRAPS
560 N Street, SW - Suite N-707
Washington, DC 20024
202-484-7707
Fax: 202-484-0616
E-mail: ctraps@radix.net

Gail Charnley
Health Risk Strategies
826 A Street, SE
Washington, DC 20003
202-543-2408
Fax:202-543-3019
E-mail: healthrisk@aol.com

David Chen
Office of Children's Health Protection   •
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW (1107)
Washington, DC 20460
202-260-7677
E-mail: chen.david@epa.gov

David Clarke
Senior Director
Regulatory Reinvention and Legal Reform Team
Chemical Manufacturers Association
1300 Wilson Boulevard
Arlington, VA 22209
703-741-5160
Fax: 703-741-6092
E-mail: david_clarke@cmahq.com

Jim Cogliano
 Branch Chief
 National Center for Environmental Assessment
 U.S. Environmental Protection Agency
Ariel Rios Building
 1200 Pennsylvania Avenue, NW(8623 D)
Washington, DC 20460
 202-564-3269
 Fax: 202-565-0079
 E-mail: cogliano.jim@epa.gov.
Vicki Dellarco
Senior Scientist
Office of Pesticides Programs
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW(7509C)
Washington, DC 20460
703-305-1803
Fax: 703-605-0646
E-mail: dellarco.vicki@epa.gov

John Doe
Principle lexicologist
Zeneca CTL
Alderly Park, Macclesfield
Cheshire SK104TJ
UNITED KINGDOM
162-551-4556
Fax: 162-558-2715
E-mail: john.doe@ctl.zeneca.com

Paul Dugard
Halogenated Solvents Industry Alliance
2001 L Street, NW - Suite 506A
Washington, DC 20036
202-775-0232
Fax: 202-833-0381
E-mail: pdugard@hsia.org

Angelina Duggan
Director of Science Policy
American Crop Protection Association
1156 15th Street, NW - Suite 400
Washington, DC 20005
202-872-3885
Fax: 202-463-0474
E-mail: angelina@acpa.org

Alvin Edwards
Program Analyst
Office of Resource Management
Office of Research & Development
 U.S. Environmental Protection Agency
Ariel Rios Building
 1200 Pennsylvania Avenue, NW (8102 R)
Washington, DC 20460
 202-564-6706
 Fax: 202-565-2908
 E-mail: edwards.alvin@epa.gov
                                             B-4

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Elaine Francis
National Program Director for
Endocrine Disrupters Research
Office of Research & Development
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW(8701 R)
Washington, DC 20460
202-564-6789
Fax: 202-565-2444
E-mail: francis.elaine@epa.gov

Steve Gibb
Managing Editor
Risk Policy Report
1225 Jefferson Davis Highway - Suite 1400
Arlington, VA 22202
703-416-8578
Fax: 703-416-8543
E-mail: steve.gibb@iwpnews.com

David Goldsmith
Associate Research Professor
Department of Environmental &
Occupational Health
George Washington University Medical Center
2300 K Street, NW - Suite 201
Washington, DC 20037
202-994-1734
Fax:202-994-0011
E-mail: eohdfg@gwumc.edu

Utpal Gupta
Project Leader, Drug Safety Evaluation
Central Research Division
Pfizer, Inc.
Eastern Point Road
Groton, CT  06340
860-441-1864
Fax: 860-441-0438
E-mail: utpal_gupta@groton.pfizer.com

Karen Hammerstrom
Acting Division Director
National Center for Environmental Assessment
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW (8601D)
Washington, DC 20460
202-564-3258
Fax: 202-565-0079
E-mail: hammerstrom.karen@epa.gov
Karen Hopfl-Harris
Associate Director for Policy
Physicians for Social Responsibility
1101 14th Street, NW- Suite 700
Washington, DC 20005
202-898-0150, Ext: 228
Fax: 202-898-0172
E-mail: khopfl@psr.org

Ann Hwang
Environment & Health Program Associate
Physicians for Social Responsibility
1101 14th Street, NW - Suite 700
Washington, DC 20005
202-898-0150, Ext: 223
Fax: 202-898-0172
E-mail: ahwang@psr.org

Sam Kacew
Department of Pharmacology
University of Ottawa
451 Smyth Road
Ottawa, Ontario K1H 8M5
CANADA
613-562-5800, Ext.: 8357

Carole Kimmel
Senior Scientist
National Center for Environmental Assessment
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennslyvania Avenue, NW (8623 D)
Washington, DC 20460
202-564-3307
Fax: 202-565-0050
E-mail: kimmel.carole@epa.gov

Jane Koska
Analyst
Shook, Hardy & Bacon
600 14th Street, NW- Suite 800
Washington, DC 20005
202-783-8400
Fax:202-783-4211
                                           B-5

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Arnold Kuzmack
Senior Science Advisor
Office of Water
Office of Science & Technology
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW(4301)
Washington, DC 20460
202-260-5821
Fax: 202-260-5394
E-mail: kuzmack.arnold@epa.gov

David Lai
Toxicologist
Office of Pollution, Prevention & Toxics
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW (7403)
Washington, DC 20460
202-260-6222
Fax: 202-260-1279
E-mail: !ai.david@epa.gov

Joan LaRock
President
Government Relations
LaRock Associates, Inc.'
6728 Baron Road
McLean, VA 22101
703-556-3324
Fax:703-734-7763
E-mail: joanlarock@erols.com

Elizabeth Margosches
Office of Pollution Prevention & Toxics
U.S. Environmental Protection Agency
Ariel Rios  Building
1200 Pennslyvania Avenue, NW(7403)
Washington, DC 20460
202-260-1511
Fax: 202-260-1279
E-mail: margosches.elizabeth@epa.gov

Carl Mazza
Science Advisor
Office of Air and Radiation
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW(6101A)
Washington, DC 20460
202-564-7427
Fax: 202-564-1407
 E-mail: mazza.carl@epa.gov
Ray McAllister
Senior Director of Science & Regulatory Policy
American Crop Protection Association
1156 15th Street, NW - Suite 400
Washington, DC 20005
202-872-3874
Fax:202-463-0474
E-mail: ray@acpa.org

Robert McGaughy
Senior Scientist
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW (8623 D)
Washington, DC 20460
202-564-3244
Fax: 202-565-0078
E-mail: mcgaughy.robert@epa.gov

Rita Monroy
Project Director
National Alliance for Hispanic Health
1501 16th Street, NW
Washington, DC 20036  .
202-797-4334
Fax:202-797-4353
E-mail: rmonroy@hispanichealth.org

Ed Norman
Head
Children's Environmental Health Branch
Environmental Health Services Section
North Carolina Department of Environment
and Natural Resources
1632 Mail Service Center
Raleigh, NC  27699-1632
919-715-3293
Fax:919-715-4739
E-mail: ed.norman@ncmail.net

Pat Phibbs
 Reporter
The Bureau of National Affairs, Inc.
 1231 25th Street, NW
Washington, DC 20037
 202-452-4106
 Fax: 202-452-7891
 E-mail: pphibbs@bna.com
                                            B-6

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Peggy Reynolds
Chief, Environmental Epidemiology Section
Environmental Health Investigations Branch
Division of Environmental &
Occupational Disease Control
California Environmental Protection Agency
1515 Clay Street - Suite 1700
Oakland,  CA 94612
570-622-4500
Fax: 510-622-4505
E-mail: preynold@dhs.ca.gov

Cindy Richard
Senior Scientist
Achieva
813 Frederick Road - Suite 200
Baltimore, MD 21228
410-788-1992
Fax:410-788-1993
E-mail: cindy@achievainc.com

Bruce Rodan
Senior Scientist
National Center for Environmental Assessment
Office of Research & Development
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avene, NW(8601 D)
Washington, DC 20460
202-564-3329
Fax: 202-565-0066
E-mail: rodan.bruce@epa.gov

Brianne  Schaffert
Aidan O'Neil Foundation for the
Prevention of Childhood Cancer
1225 Cork Drive
Papillion,  NE 68046
402-339-6411
Fax:402-399-1575
E-mail: saranrobo@home.com

Scott Schwenk
Office of Research & Development
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennslyvania Avenue, NW(8101R)
Washington, DC 20460
202-564-6667
Fax: 202-565-2431
E-mail: schwenk.scott@epa.gov
Bob Sonawane
Branch Chief
National Center for Environmental Assessment
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW (8623 D)
Washington, DC 20460
202-564-3292
Fax: 202-565-0079
E-mail: sonawane.bob@epa.gov

Anne Travisano
Student Nurse
School of Nursing
Georgetown University
4547 Indian Rock Terrace, NW
Washington, DC 20007
202-333-3227
E-mail: travisaa@gusun.georgetown.edu

Linda C. Tuxen
Office of Research & Development
National Center for Environmental Assessment
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW(8601 D)
Washington, DC 20460
202-564-3332
Fax: 202-565-0090
E-mail: tuxen.linda@epa.gov

Vanessa Vu
Associate Director for Health
Office of Research & Development
National Center for Environmental Assessment
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW(8601 D)
Washington, DC 20460
202-564-3282
E-mail: vu.vanessa@epa.gov

Megan Wallace
Office of Air and Radiation
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avene, NW (6101 A)
Washington, DC 20460
202-564-7426
E-mail: wallace.megan@epa.gov
                                           B-7

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Joanne Watters
Biologist
Novigen Sciences, Inc.
1730 Rhode Island Avenue, NW- Suite 1100
Washington, DC 20036
202-293-5374
Fax: 202-293-5377
E-mail: jwatters@novigensci.com

Chris Wilkinson
JSC, Inc.
1525 Wilson Boulevard - Suite 600
Arlington, VA  22209
703-312-8518
Fax: 703-527-5477
E-mail: chrisw@jscinc.com

Eric Wilson
Researcher
PETA
3435  R Street, NW-#8
Washington, DC  20007
202-337-1686
Fax:202-337-6097 .
E-mail: eric_w@peta-online.org

Jeanette Wiltse
Director
Office of Water
Health and Ecological Criteria Division
U.S. Environmental Protection Agency
Ariel Rios Building
1200 Pennsylvania Avenue, NW (4304)
Washington, DC  20460
202-260-7317
Fax:202-260-1036
E-mail: wiltse.jeanette@epa.gov

William Wood
Executive Director, Risk Assessment Forum
Office of Research & Development
 National Center for Environmental Assessment
 U.S.  Environmental Protection Agency
Ariel  Rios Building
 1200 Pennslyvania Avenue, NW (8601 D)
Washington,  DC 20460
 202-564-3358
 E-mail: wood.bill@epa.gov
Foster Young
Assistant Deputy Commissioner
Office of Policy & Intergovernmental Affairs
South Carolina Department of Health
and Environmental Control
P.O. Box 101106
Columbia, SC  29211-0106
803-898-0808
Fax: 803-898-0445
E-mail: youngfh@columb60.dhec.state.sc.us

Sheila Young
Student Nurse
School of Nursing
Georgetown University
1261 35th Street, NW
Washington, DC 20007
202-333-0351
E-mail: youngs2@gusun.georgetown.edu
                                             B-8

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   APPENDIX C




MEETING AGENDA

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                          Workshop Agenda

   Information Needs to Address  Children's Cancer
                                    Risk

                          Holiday Inn Arlington at Ballston
                             4610 North Fairfax Drive
                             Arlington, Virginia 22203

             Thursday, March 30, 2000 and Friday, March 31, 2000

Thursday. March 30. 2000
6:00 - 7:00 PM

7:00-7:15 PM

7:15-7:30 PM
7:30 - 7:40 PM
7:40 - 7:50 PM

7:50-8:15PM

8:15-8:30 PM

8:30 - 8:55 PM

8:55-9:10 PM

9:10-9:20 PM
9:20 - 9:30 PM
Registration

Welcome by Sponsors
Introduction of Workshop Leads
Introductions
Charge to Workshop Participants
Discussion

Sensitivity of Children to
Environmental Toxicants
Discussion.

Exposure of Children to
Environmental Toxicants
Discussion

Comments from Observers
Session Wrap-up/Logistics
Friday. March 31. 2000
8:00 - 8:30 AM

8:30 - 8:55 AM

8:55 - 9:35 AM


9:35 - 9:45 AM

9:45-10:15 AM

 &EPA
Registration

TOPIC 1: Current and Proposed
        Approaches to Assessing
        Children's Cancer Risk
        Facilitated Discussion
        Comments/Questions

Coffee Break
Eastern Research Group, Inc.

William Farland/George Lucier

Participants
Ramona Trovato, EPA
Participants

Lynn Goldman, John Hopkins

Participants

Phil Landrigan, Mount Sinai

Participants

Observers
George Lucier, NIEHS



Eastern Research Group, Inc.

William Farland, EPA
Abe Tobia, Aventis CropScience
Lauren Ziese, CalEPA
Dan Krewski, Univ. of Ottawa

Observers
                                       C-3

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Friday. March 31 continued
10:15-10: 40 AM


10:40-11:50 AM


11:50-12:00 Noon

12:00-1:OOPM

1:00-1:25PM



1:25-2:05 PM



2:05-2:15 PM

2:15-2:45 PM

2:45-3:15PM



3:15-3:55 PM



 3:55-4:15 PM

 4:15-5:00 PM
TOPIC 2: Enhanced Use of Test
         Data Related to Children's
         Cancer Risk
         Facilitated Discussion
         Comments/Questions
Shelly Tyl, Research Triangle Inst.
Mark Miller, CalEPA
Paul Foster, CUT
Frederica Perera, Columbia Univ.
Observers
Lunch
TOPIC 3: Future Directions for Retha Newbold, NIEHS
         Toxicology Testing to
         Address Children's
         Cancer Risk
         Facilitated Discussion
         Comments/Questions
 Break
 TOPIC 4: Epidemiologic/Molecular
          Epidemiology Information
          to Address Children's
          Cancer Risk
          Facilitated Discussion
          Comments/Questions

 Workshop Summary/Next Steps
George Lambert, EOHSI
David Wallinga, NRDC
Joseph DeGeorge, FDA

Observers
 Les Robison, Univ. of Minnesota
 (Ellen Silbergeld, Univ. of Maryland)
 Michael Thun, Amer. Cancer Soc.
 Lucy Anderson, NCI
 Chris Poitier, NIEHS

 Observers

 George Lucier
                                             C-4

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      APPENDIX D




CHARGE TO PARTICIPANTS

-------

-------
                           «*• Charge to workshop Participants ««

                  Information Needs to Address Children's Cancer Risk
                   Thursday, March 30, 2000 and Friday, March 31, 2000
                                           at the
                                Holiday Inn Arlington at Ballston
                                    4610 North Fairfax Drive
                                    Arlington, Virginia 22203

The purpose of the workshop is focused and derives from issues discussed in the EPA's 1999 Draft
Revised Guidelines for Carcinogen Risk Assessment.

What is the content of the ideal data set to adequately address children's cancer risk?
        The workshop participants will focus on data needed for assessing the impact of childhood
        (including in utero) exposures to carcinogens and the issues related to hazard identification and
        dose-response analyses. The participants will address not only induction of childhood cancer,
        but also increased risks of cancer during adulthood resulting from childhood exposure. As part
        of this discussion, the participants also will be asked to consider how current protocols might be
        redesigned to better answer questions related to children's cancer risk and what additional types
        of data might be brought to bear on children's cancer risk assessment.  This would include
        information that is currently collected as well as data sets using new approaches.

     What are the elements of a "cogent biological rationale," as presented in the draft revised cancer
     guidelines (July 1999 Draft), for addressing modes-of-action for children's cancer?
        Participants will address whether and how such a rationale can be made, which  is sufficiently
        health-protective of children, based  on  the kinds of data that are typically collected by and
        available to Federal and state health science agencies at the present time. These might include
        data on cancer mode-of-action, comparative pharmacokinetics and pharmacodynamics in adults
        and children, rate and pattern of exposure in adults and children, etc. The background for these
        discussions is the reality that  chemical-specific data are often lacking  to specifically address
        children's cancer risk from environmental chemical exposures.  As a consequence, the
        assessment of children's risk is  currently addressed  by evaluations of traditional  cancer
        bioassays in mature animals using sensitive  responders,  comparative biochemistry  and
        physiology between adults and developing animals and humans, and public-health-protective
        default positions in the absence of child-specific data.

     It is expected that workshop discussions will be valuable to the general risk assessment community,
     will provide input to Federal testing strategies for the future, and will  inform the public dialogue
     around children's health issues as they are addressed in the EPA's draft revised cancer guidelines.
     A summary report of the perspectives and views coming out of this workshop will be published in
     the peer-reviewed, scientific literature.
                                               D-3

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            APPENDIX E




OVERHEADS USED IN THE PRESENTATIONS

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              Overheads from
Welcome and Charge to Workshop Participants
   (William Farland and Michael Firestone)
                     E-3

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   Charge to the Children's Cancer
         Workshop Participants
         United Stales
         Environmental Protection
          toney
                           Of free of iChilclr
                      Ramona Trovato,
                      Director

                      Thursday, March 30,2000
                EXECUTIVE ORDER
  PROTECTION OF CHILDREN FROM ENVIRONMENTAL
          HEALTH RISKS AND SAFETY RISKS
                   April 21, 1997
"... each Federal agency:
(a) shall make it a high priority to identify and
assess environmental health risks and safety risks
that may disproportionately affect children; and (b)
shall ensure that its policies, programs, activities,
and standards address disproportionate risks to
children that result from environmental health risks
or safety risks."
                     E-5

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    Role of the Children's Cancer
        Workshop Participants	
The intent of EPA and NIEHS in sponsoring
this workshop is to obtain individual views
and perspectives from the participants.
Because we have not chartered this group
under the Federal Advisory Committee Act
(FACA), we are not seeking consensus
recommendation from the participants.
   Focus of the Children's Cancer
              Workshop
   •The main focus of this workshop is to
    discuss children's cancer risk
    assessment and related data needs.

   •A secondary focus is to address issues
    that have arisen during review of EPA's
    1999 Draft Revised Guidelines for
    Carcinogen Risk Assessment.
                  E-6

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      Specific Issues for Discussion
1.  Characterizing the content of the ideal data
   set to adequately address children's cancer
   risk, focusing on data needed for assessing
   the impact of childhood (including in utero)
   exposures to carcinogens and the issues
   related to hazard identification and dose-
   response analyses
      Specific Issues for Discussion
    Addressing not only induction of childhood
    cancer, but also increased risks of cancer
    during adulthood resulting from childhood
    exposure.
                  E-7

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  Specific Issues for Discussion
Considering how current cancer bioassay
testing protocols might be redesigned to
better answer questions related to
children's cancer risk and what additional
types of data might be brought to bear on
children's cancer risk assessment.
   Specific Issues for Discussion
Defining what are the elements of a
"cogent biological rationale," as presented
in the draft revised cancer guidelines, for
addressing modes-of-action for children's
cancer.
                E-8

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      Specific Issues for Discussion
5.  Answering whether and how a "cogent"
   rationale can be made, which is sufficiently
   health-protective of children, based on the
   kinds of data that are typically collected
   by and available to Federal and state health
   science agencies at the present time.
6.
      Specific Issues for Discussion
Defining what additional data, such as
cancer mode-of-action, comparative
pharmacokinetics and pharmacodynamics
in adults and children, rate and pattern of
exposure in adults and children, etc., might
be useful in developing a "cogent"
rationale.
                   E-9

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      Specific Issues for Discussion
7... Addressing whether the assessment of
   children's risk, as it is currently conducted
   by evaluations of traditional cancer
   bioassays in mature animals using sensitive
   responders, is sufficiently public-health-
   protective in the absence of child-specific
   data.
      Communicating the Children's
       Cancer Workshop Discourse
  EPA and NIEHS will assist the workshop
  participants in publishing a summary report
  of the perspectives and views coming out of
  this workshop in the peer-reviewed, scientific
  literature.
                 E-10

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               Overheads from
Sensitivity of Children to Environmental Toxicants
               (Lynn Goldman)
                    E-ll

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 Sensitivity of  Children to
 Environmental Carcinogens

      Lynn R. Goldman, M.D., M.P.H.
Public Health Issues
    Childhood cancer and potential causes
    Childhood carcinogenesis
                 E-13

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Childhood cancer issues	

   + Low rate of occurrence and controversy
     about trends
   + Unique cancer types
   *• Very short latency
   *• Many known genetic and familial
     associations
   + High probability of gene/environment
     etiologies
Childhood Cancer: Trends

    + Childhood cancer mortality is decreasing, yet:
    + Between 1973 and 1991 the rate of cancers for
      children under the age of 15 increased at about
      1% per year.*
    + Infants (< 12 months of age) are at relatively
      high risk (22 cancers per 100,000 per year).
    4 For infants, the increase between 1973 -1992
      was 3% per year.
            « The National Cancer Institute is expected to update these statistics in the very
             near future.
                     E-14

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 Childhood Cancer Trends
                     Year
    -^-0-4 -«-"5-9" -*-'10-14" -B-15-19'
Childhood ALL and Brain cancer:  1973-96
Ra
                  E-15

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Childhood carcinogenesis

   * Is childhood a time of greater susceptibility
     to carcinogens?
   + Specific examples that raise concerns:
      - DES exposures
      - Radiation induced cancers (especially leukemia
       and breast cancer)
      - Smoking initiation and lifetime risk for lung
       cancer
 Environment and cancer

    + Probably a small percentage of cancer
      solely or in part due to environment
      (estimates range from 5-25%)
    «• This is however a large public health
      burden
    4- 540,000 deaths from cancer 1998
    4- Range of 27,000 to 134,000 environmental
                    E-16

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Susceptibility issues re:  the
rodent bioassay model	

    * Genetic susceptibilities
      - Inherited predisposition genes
      - Polymorphisms in pharmokinetics affecting dose
    * Reduced time to tumor (latency) resulting from
      rapid growth of tissues
    + Persistence of effects (e.g. mutations and
      alterations of cell differentiation)
    + Nutritional factors
    * Hormonal factors
                       E-17

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       Overheads from
Children's Environmental Health
       (Lynn Goldman)
            E-19

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Children's Environmental Health

Children are not little adults
A life cycle approach to understanding
environmental risks to kids
Birth defects as a possible early report
Other possible reports: childhood cancer
and childhood asthma
  Children are not little adults
  Exposure
  Metabolism
  Growth and Development
  Shelf Life
                 E-21

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  Children are more exposed

They breathe more air, drink more water
and eat more food, pound for pound, than
adults.
Children play close to the ground, where
some pollutants concentrate.
Normal hand-to-mouth activity exposes
kids to pollutants in dust and soil.
     Children have different
           metabolism
 They may be more or less capable of
 breaking down, excreting, inactivating, or
 activating toxic substances. These
 differences should be taken into account.
                 E-22

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   Children's rapid growth and
     development make them
            vulnerable
 Organ systems - central nervous system,
 reproductive organs, immune system, and
 lungs - are more susceptible to toxic
 insult at various phases of development.
Children have a longer shelf life

• With more future years for disease to
 express itself, diseases with long latency
 periods or requiring chronic exposure may
 have more serious impacts.
               E-23

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Introduction - Dioxins & PCBs

        PCB's = two linked phenyl rings + Cl
        PCB's: industrial uses '30s - '70s
        Dioxins & furans = contaminants from combustion &
        manufacturing practices;
        Long half lives (persistent), bioaccumulate, varying
        toxicity
        Most toxic is 2,3,7,8-TCDD (contaminant of Agent
        Orange)
Example:  Exposures to dioxins
        from birth to age 25
           Cumulative consumption of dioxins
               newborn-25 years - males
                         10     15
                         Age (years)
                                      20
                                             25
      Source: Patandin et a). Environmental Health
      Perspectives, 107:1,1999.
                    E-24

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  Example:  Babies have higher
      dioxin doses than adults
           Dosage of dioxins (TEQ) by age- males
         120

         100

         80

         60
       8 40
       D
         20

         0
                   10   IS
                     Ago
                            20
      Source: Potandin et a!. Environmental Health
      Perspectives. 107:1,1999.
Intake Rates:  Adults vs Children

•  Drinking water
•  Food
•  Soil
•  Air
                 E-25

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       Drinking Water
          Drinking water consumption by age (high end)
   90 T—
                 age 1-10    age 11-19      adult

                     Age group
                 Food
  200-
  180-


  160-
  140-

a-120-
2 ioo
CT
E  80
   60
   20


   0
Wn m-n B-
J   J
                                 i i , II • i i ,
       <1    1-2   3-5   6-11  12-19  20-39  40-69  70 +

               [•meat • dairy a eggs atlsh|
                  E-26

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           Child (10kg)
Adult (70kg)
                   113 Mean B High end]
                     Air
Newborn  Infant (1 yr) Children(1-   Females    Males (13-
                         12)       (13-65)       65)
              I Meter3/kg-day B Liters/kg-min |
                    E-27

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               Overheads from
Exposure of Children to Environmental Toxicants
              (Philip Landrigan)
                    E-29

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         DIETS  OF
         INFANTS
         AND
         CHILDREN
     1.2%Vover that'^ioa,
17.3% (the latter increase was       ''
                             -
scended testes, inguinal hernia, and prenatal factors have been implicated
as possible risk factors, the cause of the trend is unknown.   ' •'
Incidence rate per 100,000*
'6 •
         White mule*
   1 ' 1Mr~i iii »""-i — (—'i ..... •) — r— T-— i—-i — i — i — i — i — i "— i--r
 1973 1975 1977 1979 1981 1983 1985 I9B7 1989 1991 1993 1995
             Year of diagnosis
                   l Ca*crr Katti anJ Ruks. JAeditio*
             E-31

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                     HTf POSFRQISS/EPISPSQ1 flS
            TRENDS IN REPORTED INCIDENCE.  BT QUHRTER OF BIRTH.
               BIRTH DEFECTS MONITORING PROGRFW / CPHH
                        JHH 1970-DEC 1993
                     IBRTES PER 10.000 70TRL BIB1H31

                      „  -•  . QUBRTERLT RHTES
                          a-TERB MOVING HVERflGE
       70 71 72 73" 7« 75 78 !7T 7B 73 00 81 02 OS BM BS 88 87 SB 63 BO 31 BZ 93
                 !      '      YEBB OF BlfltH
                Incidence of Childhood  Cancer
New Cases
 1   per
 100,000/yr
                 i 1972       1976       1980       1984       19813

Incidents of cancer In white children by calendar year of diagnosis, 1973-1988, United States, SEER
(data from Table 11-21 In the original report). The correlation coefficient, r, Is 0.542.  j
                                 E-32

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          Prevalence Rate^ for Asthma by Age
          and Year, United States, 1984-1994
 Rate per
  1000
population
           '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95
       Source: Centers for Disease Control & Prevention
             Examples'of the  "  '•
        New Pediatrio Morbidity
                                    
-------
The "New Pediatrics Morbidity!'
A range of chronic conditions of   ;
complex and poorly defined origin
that account for most hpspitalizations
and deaths among American children
today.                           ;|
        Chemicals with medium/high
         potential human exposure:
         proportion with minimum
             screening data
                 E-34

-------
E-35

-------
% CoKguEsr cf PssmERCE ia. NEW YORK CITY ~
^crftShomlg the Deatft Rate i '	'  	' "'
          REGOSTOEMDATIQMS Qi
      THE HAS COW1M1TTEE     i:
                                i1
Improvfe toxicity testing

Establish new, additional 10-fold  j
uncertainty factor as a default

Collect better data on food consumption
       ^               ",          - •  "
Collect better data on pesticide residues
                E-36

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:•         • ' MAS COMMITTI

The Committee recommended that
changes be made in current regulatory
practice.

Tolerances must be based principally on
health considerations.
i
Estimates of exposure should reflect the
unique characteristics of infants and
children and should account for all dietary
and nondietary intake of pesticides.     i
 Children's exposures to pesticides are greater
 pound-for-pound than those of adults.

 Children are less well able than adults to detoxify
 most pesticides.

 Children's developing organ systems are highly
 vulnerable to pesticides.

 Children have more years qf future life in which to
 develop chronic disease triggered by early
 exposure.                             r^n
                   E-37

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EXAMPLES OF THE VULNERABILITY OF INFANTS AND CHILDREN TO
                    ENVIRONMENTAL TOXICANTS
        •  Increased risk of cancer following mitrosamine exposure (Peto)

        •  Increased risk of cancer following vinyl chloride exposure ( Drew)

        •  Decreased ability to detoxify organophosphates (Moser)

         •  Increased susceptibility to lead (Needleman)

         •  Increased susceptibility to alcohol (fetal alcohol syndrome)

         •  Thalidomide and phocomelia

         •  DBS and adenocarcinoma of vagina

         .  New possible: Neurodevelopmental toxicity of chlorpyifos (Whitney; Song;
            Campbell)
                                  E-38

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              Congressional Charge
                       to the
   NAS Committee on Pesticides & Children:
•  Are children more heavily exposed than adults?


«  Are children more susceptible to toxicity than adults?


•  Do current laws and decision practices protect children?
                 Environmental Health
                 Threats To Children
                       E-39

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                Executive Order on Protection of Children
              From Environmental Health Risks and Safety
                                       Risk
                                   luuctl April 21.199T
                                   THE WHITE HOUSE >
                                 OHicrofiac Frai Secretary
                                   Far Itnmciluic Rtteaj*
                By Jh« authority vested in ow as President by ifae Ginitiliuicn and the U« 1 of ihe L'nittd
                StattJ of America, u |i hereby ordered as faltowi:

                JfCffan /. Policy

                1.101 A growing body of Kicntitic knowtcdjc deewtuuates thai children nuy suffer
                aiiKtxMrtioriUelv from environmental health nils and safety rijLi, The« mla ante
                beJauirehildrca'i nwrolosfca!. urumnwlosical. dlfiudve. a»! other bodily tpwaa «
                j^devrfocbic rftUOrcu «! more food, dri«k mor. lluidj. and bteail* mcr= ju in
                praponioni.} UtcirboOy uvi^ht than adultr. chiIOren*« lira and vx i
                (a) jhilt males it ahif h priority W identify and awo* cnvirocuwstal health rf*U and
                riis thac raay tUtpraponiwaiely atTeu: chitdrcn: and
                00 jhall cuure -Jut tU eolEciet. prograaH. arfvities. anJ lUcdanli address
                n&s w children thai mult from «nviK>n. with its pnsvmoia.
                Sff. 2. Definition*. The following Jcfintticu dull appl> » ih» order.

                MOI. -Federal ak-«cy- nwans any authority of the Unit*! Sutw jhat is M asettcy under «
                U.S.C, 35«ll) other than tfao« eocwdeicd to be. lodepenJeni nrsuUwty iS««»« "w^J4

                Ifli XT: e»vere-d under iheauipicei of tbebepanaiett of Defense.

                2-:- action* mean* any iubnantis-e action in a rulerr-afcing. teu&taJ
                aflcr the date of th« cider ot for which a Notice of rrojuwea Rale.-nakins ^ pubtwhsd I jew
                after the tlite of thli on!cr.ihat is likely to mull ma rule ihK cuy:

                (a) br-«ocomtcal!* rigniGcaaf voter Exeswivc Order !2K6 (a ru!enu!di« that ha* as
                annual elYe« on ihe'wonMny of SI 00 rrJIlion ar nwe or »ould adversely afScet in a
                m.-ilRul «a* ihe ecenotnv. a *ecur of ihe «c9o«ay. producaviti'. compeUfion.]ow,
                ertinirjaeai. public healih « safety, ocState, \cxai. or tribal so«t=ae!iO orwmrcu
Food Quality Protection Act9'1996              ;'


Highlights of Federal Food, Drug, and Cosmetic Act


a  Health-baspd safety standard for pesticide residues in food

         - Reasbnable certainty of no harm

n  Special provisions for infants and children

n  Limits consideration of benefits of pesticides
                   j         i                            :                           H
n  Tolerances reviewed within 10 years                            ;j
                   j                                                                :\
n  Penalties for violations                                               s;

a  Provisions! for endocrine testing
                                         E-40

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                            Overheads from
Topic 1: Current and Proposed Approaches to Assessing Children's Cancer Risk
                            (William Farland)
                                  E-41

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-------
                                     An EPA/NIEHS Workshop:
                           Information Needs to Address Children's Cancer Risk
                                           March 30 and 31, 2000
                                  An EPA/NIEHS Workshop:
                                  Information Needs to Address
                                       Children's Cancer Risk
                                        March 30 and 31, 2000
                                              TOPIC 1
                           Current and  Proposed Approaches
                                           to Assessing
                                    Children's Cancer Risk
                                         William H. Farland, Ph.D., Director
                                     National Center for Environmental Assessment
                                     Office of Research and Development
                                 U:S. ENVIRONMENTAL PROTECTION AGENCY
                   Research +=* Assessment 3=± Management
                       EPA Scientific Research/
                       Data Collection
                                             Risk Assessment
                        Animal Toxicolo
                        Clinical Studies
                        Epidemiology
                        Cell/Tissue
                          Experiments
                        Computational
                         Methods
                        Monitoring/
                         Surveillance
                        Dose-Response
                        Characterization
                                              Hazard
                                               cterization
                                               Exposure
                                             Characterizati
• Other Federal Agencies
• States/Local Agencies
•Acaderrria-
• industry
 Public Interest/Environmental Groups
                                                               Non-ris
                                                               Analyses
                            External Input
                            into Research/
                            Assessment
William H. Farland, Ph.D., Director
Mailing Address:
National Center for Environmental Assessment (8601D)
Office of Research and Development
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW Ariel Rios Building
Washington, DC 20460
                                               .E-43
                                                                    Office Location:
                                                                 808 17th street, NW
                                                                        Suite 400
                                                               Washington, DC 20074
                                                                 Tel: 202-564-3322
                                                                 FAX: 202-565-0090
                                                          E-mail: farland.william@epa.gov

-------
                           An EPA/NIEHS Workshop:

                   Information Needs to Address Children's Cancer Risk

                               March 30 and 31, 2000
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Recent Emphasis Focuses on

the Use of Mode of Action Data



  "The quality of risk analysis will improve as the
  quality of input improves. As we learn more
  about biology, chemistry, physics, and
  demography, we can make progressively better
  assessments of the risks involved. Risk
  assessment evolves continually, with
  reevaluation as  new models and data become

  available."

              "Science and Judgment in Risk
              Assessment" (National Research
              Council, 1994)
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What Are Agency Risk

Assessment Guidelines?


 ^Statements of Agency policy regarding
   principles, general approaches,

   preferences, and default assumptions

   that will be applied in Agency risk

   assessments

 S Not a Cookbook

 SNota Regulation
William H. Farland, Ph.D., Director

Milling Addnss:
NaUonal Center (or Environmental Assessment (8601 D)

OIIIco of Research and Development

U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW Ariel Rlos Building

Washington, DC 20460
                                     -E-44-
                                                    Office Location:

                                                 808 17th street, NW
                                                      Suite 400
                                                Washington, DC 20074

                                                 Tel: 202-564-3322
                                                 FAX: 202-565-0090
                                            6-mail: farfand.william@epa.gov

-------
                          An EPA/NIEHS Workshop:

                   Information Needs to Address Children's Cancer Risk

                               March 30 and 31, 2000
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Guidelines Are the

Product of:


> Several Agency Colloquia

> 3 External Peer Consultation

   Workshops

> Peer Review Workshop

> Interagency Review (NIEHS,

   OSHA,FDA, NSF, DOE, NIH)

> 3 Science Advisory Board Reviews

> Public comment (> 100 commenters)
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Guidelines History
   In September 1986, EPA published

   Guidelines for Carcinogen Risk

   Assessment (5 1 FR 33992)

   1 986 Guidelines were based on the

   principles and "state of the science" as

   practiced in the  1970s and early 1980s

   1 986 Guidelines allowed for flexibility

   in application but little in the way of

   guidance on when/how to depart from

   default assumptions
William H. Farland, Ph.D., Director
Mailing Address:

National Canter for Environmental Assessment (8601 D)

Office of Research and Development

U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW Ariel Rios Building
Washington, DC 20460
                                    E-45.
                                                Office Location:
                                              808 17th street, NW

                                                   Suite 400
                                            Washington, DC 20074

                                              Tel: 202-564-3322
                                              FAX: 202-565-0090
                                         E-mail: farland.william@epa.gov

-------
                          An EPA/NIEHS Workshop:
                   Information Needs to Address Children's Cancer Risk
                               March 30 and 31, 2000
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Revision Directions for Risk

Assessment Guidelines

o  Emphasize full characterization

o  Expand role of mode of action
   information (and, therefore,
   biomarkers!)

o  Use all information to design
   dose response approach

o  Two step dose response assessment
                 EPA's Guidelines for Carcinogen Risk
                 Assessment (Draft, July 1999) state:

               "The interaction of the biology of the organism
               and the chemical properties of the agent
               determine whether there is an adverse effect.
               Thus, mode-of-actjon analysis is based on
               physical, chemical, and biological information
               that helps to explain key events in an agent's
               influence  on development of tumors.  The
               entire range of information developed in the
               assessment is reviewed to arrive at a reasoned
               judgment."
William H. Fariand, Ph.D., Director
Mailing Address:
National Center for Environmental Assessment (8601 D)
Office of Research and Development
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW Ariel Rios Building
Washington, DC 20460
                                    -E-46-
                                                Office Location:
                                              808 17th street, NW
                                                   Suite 400
                                            Washington, DG 20074
                                              Tel: 202-564-3322
                                              FAX: 202-565-0090
                                         E-mail: fariand.william@epa.gov

-------
                             An EPA/NIEHS Workshop:

                     Information Needs to Address Children's Cancer Risk

                                  March 30 and 31, 2000
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 Evolution of Hazard

 Characterization
  Hazard Identification j

  through Traditional

  Toxicologic Testing
                    Hazard Characterization

                    through Evaluation of

                    Mechanism(s) and

                    Biologically-Based Models
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Mode of Action --
     How does the chemical
     produce Its effect?


     Are there mechanistic data

     to support this hypothesis?


     Have other mechanistic

     hypotheses been considered
     and  rejected?
William H. Fariand, Ph.D., Director

Mailing Address:

National Center for Environmental Assessment (8601 D)

Office of Research and Development

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW Ariel Rios Building
Washington, DC 20460
                                      E-47
                                                   Office Location:

                                                 808 17th street, NW
                                                      Suite 400
                                               Washington, DC 20074

                                                 Tel: 202-564-3322
                                                 FAX: 202-565-0090
                                           E-mail: fartand.william@epa.gov

-------
                           An EPA/NIEHS Workshop:

                   Information Needs to Address Children's Cancer Risk
                                March 30 and 31, 2000
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Use of Mode of Action Data

in Dose Response Assessment


o Construct a biologically-based or case

  specific model

o Link dose response curve for precursor
  effect to dose response for tumor effect

o Use dose response for other effect in
  lieu of that for tumor effect if it is judged
  to be a better measure of potential risk

o Use to inform assessment of  possible
  dose response in range of extrapolation
                  Dose Response Assessment
                       &ooafa.t^1a*&F&^^&&$:3rteL&.*
                                                          Range of
                                                          Extrapolallor
William H. Fartand, Ph.D.. Director
MsiHng Address:
National Center for Environmental Assessment (8601 D)
Office of Research and Development
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW Ariel Rios Building
Washington, DC 20460
                                                    Office Location:
                                                 808 17th street, NW
                                                      Suite 400
                                                Washington, DC 20074
                                                 Tel: 202-564-3322
                                                 FAX: 202-565-0090
                                            E-mail: fariand.william@epa.gov

-------
                              An EPA/NIEHS Workshop:

                      Information Needs to Address Children's Cancer Risk
                                   March 30 and 31, 2000
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Decision  Logic for

Dose Response  Assessment


• Linear

  + DNA reactive or other evidence supporting linearity

  + not DNA reactive but insufficient data to characterize

    a non-linear mode of action

• Non-linear

  + not DNA reactive or otherwise linear, and sufficient

    data to characterize a non-linear mode of action

• Both

  + differing activity at different sites

  + complex activity needing both approaches
    to describe
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 Linear Approach is Public

 Health Conservative

• When the linear approach is used to

  extrapolate several orders of magnitude

  from observed data, EPA does not find

  a need to add an adjustment for human

  variability

• The NRC did not consider the  overall

  effect of extrapolation to low doses

   + PBPK models or scaling adjustment are
     to be applied to account for interspecies
     differences in toxicokinetics
William H. Fariand, Ph.D., Director
Mailing Address:

National Center for Environmental Assessment (8601 D)
Office of Research and Development

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW Ariel Rios Building
Washington, DC 20460
                                       E-49
                                                     Office Location:

                                                   808 17th street, NW
                                                        Suite 400
                                                 Washington, DC 20074
                                                   Tel:  202-564-3322
                                                   FAX: 202-565-0090
                                             E-mail: farland.william@epa.gov

-------
                            An EPA/NIEHS Workshop:

                    Information Needs to Address Children's Cancer Risk
                                 March 30 and 31,2000
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 Linear Approach is Public Health

 Conservative (continued)

* Low dose extrapolation is conducted on the

  Point of Departure, the lower 95% confidence

  limit on the lowest dose associated with

  increased tumor response in the observation

  range (e.g., LED10)

*• Under standard experimental conditions at

  maximum tolerated dose, the test rodents are

  considered to be stressed, not "average",

  animals

*• The straight line approach results in risk

  estimates similar to those by the IMS

  procedure -- likely to overestimate at low
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 Human Variability —

 Linear Approach

• The linear low dose extrapolation procedure

  is assumed to be very public health

  conservative without need for additional

  factors to account for human variability

• The NRC (1994) suggested that "average

  rodent" to "average human" extrapolation

  may not account for variability adequately

  when making estimates of individual risk

  (maximum  exposed individual(s) for a site

  assessment), but is adequate for incidence

  estimates for a population
William H. Farlaml. Ph.D.. Director
Mailing Address:
National Canter for Environmental Assessment (8601 D)

Office of Research and Development

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW Ariel RIos Building

Washington, DC 20460
                   E-50
                                                     Office Location:

                                                   808 17th street, NW
                                                        Suite 400
                                                 Washington, DC 20074
                                                   Tel: 202-564-3322
                                                   FAX: 202-565-0090

                                             E-mail: farland.william@epa.gov

-------
                            An EPA/NIEHS Workshop:

                     Information Needs to Address Children's Cancer Risk
                                 March 30 and 31, 2000
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 Human Variability—

 MOE Analysis
 IA margin of exposure (MOE) analysis is used

  as a default approach when application of the

  framework for mode of action (MOA) supports

  a nonlinear MOA for adults and children


 i Unless there is agent-specific data indicating

  differential responses in children, the usual

  factor for human variability is used and an

  additional factor to protect children is not

  applied (dose adjustment is made for

  children)
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Proposed Approach to

Children's Risk



• Potential differences in exposure, dose,

  and response between children and
  adults

• A case-by-case approach based on

  weight of evidence

• Default science policy positions and

  procedures to be used in the absence
  of data
William H. Farland, Ph.D., Director

Mailing Address:

Natfonal Center for Environmental Assessment (8601D)
Office of Research and Development

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW Ariel Rios Building

Washington, DC 20460
                                     -E-51-
                                                  Office Location:
                                                808 17th street, NW

                                                     Suite 400
                                              Washington, DC 20074
                                                Tel: 202-564-3322

                                                FAX: 202-565-0090
                                           E-mail: fariand.william@epa.gov

-------
                            An EPA/NIEHS Workshop:

                    Information Needs to Address Children's Cancer Risk
                                 March 30 and 31, 2000
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Early Life Sensitivity


• Guidelines call for a separate evaluation

  when there are data indicating increased

  sensitivity to early-life exposure (section

  2.2.2.2)

• Case example (Appendix F) illustrates how

  such information can be used to

  characterize and estimate risks for early-

  life exposure

• The proposed approach calculates an

  adult and a childhood-specific unit risk

  estimates
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Childhood Risks -

Default Procedures


* Slope factors and unit risks for lifetime

  exposure incorporate exposure factors

  based on adults

• In the absence of childhood-specific unit

  risk, and there is a need to assess risks

  from childhood exposure, adult unit risk

  is used after adjustment for potential

  differences in dose between adults and

  children (section 3.5.2)
W»!am H. Fartand. Ph.D.. Director
Mailing Address:
National Canter (or Environmental Assessment (8601 D)
Olllco of Research and Development
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW Ariel Rios Building
Washington. DC 20460
                                       E-52-
                                                   Office Location:
                                                 808 17th street, NW
                                                      Suite 400
                                               Washington, DC 20074
                                                 Tel: 202-564-3322
                                                 FAX: 202-565-0090
                                            E-mail: fariand.william@epa.gov

-------
                            An EPA/NIEHS Workshop:

                     Information Needs to Address Children's Cancer Risk

                                 March 30 and 31, 2000
                  Adult to Child  Dose

                  Adjustments


                  • Default procedures for adult to child risk

                    adjustments based on differences in dose

                    •=>  Oral slope factor - no adjustment is proposed

                    <=>  Inhalation unit risk (gases) - adjustment based
                       on body weight and breathing rate

                    ^  Drinking water unit risk - adjustment based on body
                       weight and drinking -water rate

                  m Guidance for inhaled particles, and dermal

                    exposure to be developed

                  • Are these default procedures appropriate?
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 Dose Response--

 Children


•  Dose response approach to be informed
   by evaluation of MOA information

•  When a postulated MOA is supported

   for adults but not for children, a linear

   low dose extrapolation will  be used

   as a default approach for the general

   population (including children as

   sensitive subpopulation)
William H. Farland, Ph.D., Director

Mailing Address:

National Center for Environmental Assessment (8601 D)
Office of Research and Development

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, NW Ariel Rios Building

Washington, DC 20460
                                      „ -_
                                      E-JJ
                                                  Office Location:

                                                808 17th street, NW

                                                     Suite 400
                                              Washington, DC 20074

                                                Tel: 202-564-3322
                                                FAX: 202-565-0090
                                           E-mail: farland.william@epa.gov

-------
            An EPA/NIEHS Workshop:

     Information Needs to Address Children's Cancer Risk
                 March 30 and 31, 2000
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Mode of Action--

Children

• When sufficient information is developed to
  show a MOA that is expected to be
  relevant to adults, an evaluation will be
  made as to whether this MOA is relevant
  to children

• When there is no information on children,
  or there is no cogent rationale supporting
  the comparability between responses in
  children and adults, the postulated MOA
  for adults is not considered applicable to
  children
D
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 Upcoming Events


 0 Fall 1999 - Agency and Interagency

    Review

 D Early 2001- Publish Final Guidelines

 D Other Related Activities

    + Peer review of standard computer

     algorithm (Fall 2000)

    * Development of supplementary guidance

     on Margin of Exposure analysis

    + Develop supplementary guidance on the
     assessment of children's risk
                                                     Office Location:

                                                   808 17th street, NW
                                                       Suite 400

                                                  Washington, DC 20074
                                                   Tel: 202-564-3322
                                                   FAX: 202-565-0090
                                              E-mail: fartand.william@epa.gov

-------
                            Overheads from
Frederica Perera's Comments on Topic 1: Current and Proposed Approaches to
                    Assessing Children's Cancer Risk
                                 E-55

-------

-------
 Table 2. Mean biomarker levels for mothers and newborns and mean differences in biomarker
        levels between mother-newborn pairs among all subjects (N = 160 pairs)
Biomarker
PLASMA COTININE (ng/Hll)
PAH-DNA ADDUCTS
(per 108 nucleotides) "
PAH/ AROMATIC DNA ADDUCTS
(per 108 nucleotides) c
HPRT MUTANT
FREQUENCY (X 10"6)
Mothers
Mean ± SD (n)
8.3 ±24.5 (158)
6.4 ±9.2 (135)
14.0+14.9(139)
22.1 ±25. 6 (67)
Newborns
Mean ± SD (n)
14.0 ±35.3 (160)
7.6 ±9.6 (135)
16.0+12.2(139)
8.4 ±33.7 (64)
Mother-Newborn Pairs
P-value (n pairs) "
< 0.001 (n = 158)
0.131d(n=112)
0.002" (n= 122)
< 0.001 (n = 48)
" Difference between mother and newborn biomarker level assessed using Wilcoxon Signed Ranks Test
b Measured in white blood cells by ELISA
c Measured in white blood cells by 32P-postlabeling
d Dose of PAH to the fetus estimated be approximately one-tenth of the dose to the mother
                                                        AACR 2000
      Columbia Center for Children's Environmental Health

  Vulnerability of the Fetus and Child

  Exposure                                      Effect

Lead (Needleman et al.,1979)                        D

Radiation (SMmizu et a/., 1991)                     C

Pesticides (NAS, 1993)                            D,C

PCBs (Jacobsen andJacobsen, 1996)                 D

Polycyclic aromatic hydrocarbons (PAH)     D,G
    (Perera, Whyatt et al., 1998)


                 D - Developmental    C - Cancer    G - Genetic damage
                              E-57

-------
Biomarkers in Children Stratified by Ethnicity
Cotinine
(ng/ml)

A. African-American Mean 5.64
N 13
SD1 12.9
B: Hispanic Mean 1.82
N 96
SD 2.50
A>B, adjusting for ETS P=0.059
exposure
1 SD, Standard
Deviation
4-ABP-Hb
(pg/g)

26.3
4
5.08
32.8
47
16.7
p>0.1



PAH-
aibumin
(fmol/g)
.550
13
.369
.356
93
.504
P=0.021



SCE


9.80
9
1.86
9.83
55
2.34
p>0.1



                                     TABLE 4
          PAH-DNA ADDUCT LEVELS8 STRATIFIED BY CYP1A1MSPIRFLP
 Placental Tissue

 Infant WBC
CYP1A1 Mspl-l-


7.8 ±0.6 (125)

7.1 ±0.9 (106)
CYP1A1 Mspl+/-, +/+


11.1 ± 1.5 (30)"

9.8±2.2(28)c
a mean±SE per 10s nucleotides (n)

b beta = 0.5, < 0.01
c beta = 0.5, p = 0.06 MspI+/-,+/+ vs Mspl-/- controlling for smoking status, place of
residence, coal use, dietary PAH, home/occupational exposures.
                                       E-58

-------
                        Overheads from
Topic 2: Enhanced Use of Test Data Related to Children's Cancer Risk
                         (Rochelle Tyl)
                            E-59

-------

-------
    Information Needs to Address Children's Cancer Risk
             Holiday Inn Arlington at Ballston
     Thursday, March 30, 2000 and Friday, March 31 ,.2000
                   Topic 2
  Enhanced Use of Test Data Related
        to Children's Cancer Risk
                    Presented by
                  Rochelle W. Tyl
              Research Triangle Institute
              Research Triangle Park, NC
                             f
   Reproduction Study Endpoints:
Two-generation (QPFFS 870.3800)
                          *,
                     ladices
 Mating Index
 Fertility Index         '
 Pregnancy Index
 *Precoital interval m days
 Gestational length in days
 Prenatal (postimplantation) loss
 Estrous cychcity     -   ^ ^
   cycle length m days  ^ f •>
   # (%) cycling/not cycling,
   abnormal cycles " -"^t
•* Stillborn Index
\ Etve birth Index
^.Survival Indices
  ^ %

    PND 0-4 (precull)
   ~PND4-7(postcull)
   r PND 7-14 (postcull)
   * PND 14-21 (postcull)
   ; 'lactational (PND 4-21;
   4    postcull)
                      E-61

-------
  Information Needs to Address Children's Cancer Risk
            Holiday Inn Arlington at Ballston
    Thursday, March 30, 2000 and Friday, March 31, 2000
Reproduction Study Endpoints-2

                     Offspring

 Sex ratio at PND 0,4,7T14,21

 # Males, females/litter
 Pup body weight by sex/litter at PND 0,4,7,14, 21

 Onset of puberty:

       Age at acquisition of vaginal opening
             (VOXfemales), * ~
             Weight atacquisition (ANCOVA)
       Age at acquisitionjof preputial separation (males)

             Weight at acquisition (ANCOVA)
                      V.
       * Age at first estru& (PN^D age & time from VO in
             days    •  ^i  , '! *
               "      f Bf    !,>•>-
       Anogenital distancaand body weight by
       individual pup on END 0 (triggered in F2 if
       developmental/reproductive effects present in Fl)
oints-3
Reprpdiip
                   *
 FQ. Fl.
                         gSWS^^^^Vi ll'"" -;'  . ' ,
                                     seminal
                                   glands, prostate,
                                oviducts, uterus plus
            ;  eeEwp|^^^c ejsmis at necropsy

            '  Bcift^^Sl^rV Sidneys, spleen, brain
            '* :-KQik!^fff^^^i> ^ <    ,  .   x
              (plus taiget|)rgans, gross lesions)
            •": ^;*?««SS|sS@P^*Vv^  '
              Weia^ngisiluiMb 3/sex/litter)
                              , spleen, target organs
                        E-62

-------
  Information Needs to Address Children's Cancer Risk
            Holiday Inn Arlington at Ballston
    Thursday, March 30, 2000 and Friday, March 31, 2000
Reproduction Study Endpoints-4

                    Necropsy-2
      Histopathology      >
            Parental animals
            Males: 10/group: high dose anS control
             one testis (GMA plastic, PAS/H)
             all remaining organs (paraffin, H&E)
            Males: unsuccessful breeders
                    H. i, i,^ ^ ^.
            Females: 10/group: high dose and control
             ovaries^ step-'sections-namber of primordial
             follicles  „ 7<- *r v
             all remaining organs
            Females: unsuccessM breeders
                      E-63

-------
  Information Needs to Address Children's Cancer Risk
             Holiday Inn Arlington at Ballston
    Thursday, March 30, 2000 and Friday, March 31, 2000
 Prenatal Developmental Toxicity Endpoints

                (OPPTS 8703700)

  Exposure duration: GDO/6 to term

  Maternal parameters: ' -
         Mortality (#,%)
         Body weight, weight change
        • Feed consumption (g/day; g/kg/day)
  Gestational parameters:
         # ovarian corpora lutea/dam or doe

         # total (resorptions^dead fetuses, live fetuses)
                implants/litter .

         % preimplantation loss/litter  >

         % postimplantation loss/litter

         # (%) nojn-live (resorptions plus dead
         fetuses) implants/litter
         # (%> affectedYnon-Iive plus malformed)
         implants/litter v   '  }   *'    ,
         ,
Prenatal Deyelpppr "
 _--  .  ;
 Offspring •••-;-V;MgS
        ti >^w-v *»i -•. 'Ji-T^*!r.T:t*.«-i.i-is**«?r*i;Dt»
       #EelusfeS::i«^
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   iS'Jwsttif"^^..'"'.!?jali1-',;.^"' "'

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  ||lEisifea^eig^.all.
  |pg|i^^a|Kjrmations/


^^£t&&f^-^' '• • \'
|^S|fe^tftVg¥ ;.?.>	
                         E-64  .

-------
    Information Needs to Address Children's Cancer Risk
                Holiday Inn Arlington at Ballston
      Thursday, March 30, 2000 and Friday, March 31, 2000
    Combined Chronic/Carcinogenicity Study
                    (OPPTS 870.4300)
Duration of exposure. 18 months (mouse); 24 months (rat)
Age at onset of study Young adult (6-8 weeks)
Dose groups: Control and at feast three treatmentgroups, including
           MTDandNO(A)EL
Evaluation times:  12 months and termination of study
In-life parameters evaluated:         , "' ^
       Clinical/functional observations /_ f
       Ophthalmological examination, ™  * f
       Body weight^weight gauiu „ ^ ^ -^        :.
       Food/water consumption  *•   *-  *
                                "-iv        .; ,
       Hematology, clinical chemistry, unnalysis    •:
                         .'<•*.'*& *3*. *
   Combined Chronfc/Carcin©^enicity Study-2
Gross necropsy       ^   ^l
       Organ wet weights:  -T -1*
             Liver, kidney ,^o!renals; testes, epididymides,
             o vanes, uteras; spleen,"nbranv heart, lungs (if
             inhalation sftidy) v " f »T^  / _
       Gross observations:  !v
                              .
                             '
                           ,,
             Tissues nojed above, jjlu&"bthers from digestive,
      nervous, glandular, respttatoiy/bardiovascular/
      hematopoietic, urogenitaj sjfsteins, all gross lesions and
      masses, skin        ^^
                            *    ]-
                           E-65

-------
   Information Needs to Address Children's Cancer Risk
              Holiday Inn Arlington at Ballston
     Thursday, March 30, 2000 and Friday, March 31, 2000
  Combined Chronic/Carcinogenicity Study-3

Histopathology
      Full histopathology on organs and tissues noted above-
            on all control and high dose animals and all
            animals dying or killed during study
            on animals in other dose groups, as appropriate
      All gross lesions in all animals
      Target organs in all animals
                      - *    1
   90-Day Toxicity Study in Rodents
             (OPFfef£()\3100)
 Duration of exposure: 90 djys^lS^weeks)
 Age at onset of study: Young\a|u|f^6-8 \yeeks)
 Dose groups: Control and atleasftfiree treatment groups,
       including MTD and NO(X)EL
 Evaluation time: at 90 days I ^j^ v<
 In-life parameters evaluated,' gross necropsy and
 histopathology requirements^are same as for chrome
 component of 870.4300  I<|""' °*
                         E-66

-------
   Information Needs to Address Children's Cancer Risk
              Holiday Inn Arlington at Ballston
     Thursday, March 30, 2000 and Friday, March 31, 2000
            Immunotoxicity

                 (OPPTS 870.7800)
Duration of exposure: >28 days (may be incorporated in
                          90-day or chronic study)
Age at onset of study: Young adult rodent (6-8 weeks)
Dose groups: Control and at least three treatment groups,
       including MTD and NO(A)EL              F
Evaluation time: at >28 days
                        JU- ^ -* >-
In-life parameters evaluated:    f"    t
       Clinical observations, body weight, food/water consumption
Immunotoxicity functional tests: Either the antibody plaque-forming
cell (PFC) assay or immunoglobulin quantification using the enzyme-
linked immunosorbent assay (ELIZA)  ,-
                      ^ „ \ F  ^  ~
Phenotypic analysis of total B ceU/jtotal T cell, T cell subpopulations
from spleen or peripheral blood by flow cytometry
                         *
  MetalpoligU^^^^g^c^iiietics
Duration
Age at
Dose groupsi
Evaluation time: iip> to@f
Parameters
          'scit-^-S weeks)

            •
             onrpercent^p(^KeS®$admihistered dose from
             eces,.'exhal^^^P^^|&^:.;
             ^«*wi^iK^lft^^^^S«S'i.;r''".'
                            .,,. .-
     Tissue
     unchanged testsubSiffli^lMinetabdltes in excreta
               ' ' ^'''' "  '
                        E-67

-------

-------
            Overheads from
Topic 3: Future Directions for Toxicology
Testing to Address Children's Cancer Risk
           (Retha Newbold)
                  E-69

-------

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                          E-79
Neonatal DES treatment (2fig/pup/day on days 1-5) induces uterine
adenocarcinoma in 95% of the mice that are 18 months old or older.

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                                  E-89

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                          Overheads from
David Wallinga's Comments on Topic 3: Future Directions for Toxicology
              Testing to Address Children's Cancer Risk
                               E-91

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                Toxicology Testing & Children's
                            Cancer Risk
                          David Wallinga, M.D.
                         Public Health Program
                    Natural Resources Defense Council
                            March 31, 2000
                Cancer Assessment is Data Poor
                > 80,000 registered industrial chemicals
                > 2,863 HPV chemicals produced at
                 greater than 1 million pounds per year
                > For 75%, EPA has no developmental
                 toxicity information at all (Goldman 1999)
                 63% of high volume chemicals lack any
                 test of carcinogenicity (EOF 199?)
                 523 pesticides registered in food/feed
                           Natural Resources Defense Council
David Wallinga, M.D.
E-93

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                  National Research Council, 1993
                 "In general, the committee found that current and past
                 studies conducted by pesticide manufacturers are
                 designed primarily to assess pesticide toxicity in sexually
                 mature animals. Only a minority of testing protocols have
                 supported extrapolation to infant and adolescent animals.
                 Current testing protocols do not, for the most part,
                 adequately address the toxicity and metabolism of
                 pesticides in neonates and adolescent animals or the
                 effects of exposure during early developmental stages and
                 their sequelae in later life. (Pesticides in the Diets of
                 Infants & Children, p. 4)

                                Natural Resources Defense Council             3
                  NRC & Children* s Susceptibility


                  • The NRC (1993) marshaled ample scientific
                    data suggesting that infants and children,
                    generally, have greater susceptibility to the
                    toxic effects of chemicals....
                  •  .. .Even if complete testing for individual
                    chemicals to characterize these risks to
                    children is usually lacking.
                                 Natural Resources Defense Council
David Wallinga, M.D.
E-94

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                           Sources of Children's
                      Susceptibility to Carcinogens
                  > Differences in inhalation & absorption.
                  1 Differences in activation and detoxification, combined
                   with relative immaturity of protective mechanisms,
                   such as immune system and blood-brain barrier.
                   Inherent vulnerability of rapidly dividing and growing
                   cells, as well as developing organs.
                   Differences in diet and behavior.
                                Natural Resources Defense Council
                    Importance of Strong Defaults
                          ' :ra:*s*R:i*BaBiBi1^^

                   A child's general susceptibility to toxic
                   chemicals, in the face of data gaps on
                   individual chemicals,  leads to the need
                   for...
                    • Strong, health-protective default
                      assumptions in cancer risk assessment
                    • High hurdles for abandoning these defaults
                               Natural Resources Defense Council
David Wallinga, M.D.
E-95

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                  Implications for Cancer Risk
                        Assessment Today
                          • ----^--^SECT»g»'»»^"™*»'°" •""'"L"m"""'"" "' "'"

                 Default assumptions in the proposed
                 Cancer Risk Assessment Guidelines
                 need to be closely examined
                 Claims that current defaults are health-
                 protective should be backed up by data
                 ~  Example: the Guidelines currently
                    have no default for human variability.
                             Natural Resources Defense Council
                 Implications for Future Testing
                        ^^^•••••••••••••••••i	 J J!U'"_^^££S--g,

              • Extend developmental toxicity tests beyond birth, to
                account for latency.
              • Assess cancer risk from pre-conceptual exposure.
              • Look at effects of short-term carcinogen exposure
                during developmental windows.
              • Require pharmacokinetics in immature animals.
              • Build developmental windows of vulnerability into the
                testing paradigm.
              • Validate & test for endocrine disruption.
              • Do semiquantitative assessments of cumulative risk
                             Natural Resources Defense Council             8
David Wallinga, M.D.
                                    E-96

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                              Pharmacokinetics
                   "Critical to the interpretation and extrapolation of data
                   on developmental toxicity is an understanding of the
                   Pharmacokinetics of chemicals in the developing
                   system and the complexities of direct and indirect
                   developmental exposures during pregnancy, lactation,
                   and to neonates by various routes of
                   exposure... .Guidelines for appropriate
                   pharmacokinetic information relevant to pre- and
                   postnatal exposures are needed."
                   -- Report of the EPA Toxicology Working Group of the 10X Task
                   Force, April 1 999.
                                 Natural Resources Defense Council              9
                    Developmental Carcinogenesis
                           ' • •^^•'•••••••^•••^••••••••^•••••l tULLBOBSSK V. v. ••

                    "Likewise, no specific standardized guidelines
                    exist for second tier testing on chemicals that
                    are suspected to enhance carcinogenic
                    response following perinatal exposure.
                    Experience with testing agents for
                    carcinogenic potential following exposure
                    during development is very limited to date."
                    Report of the EPA Toxicology Working Group of the 10X Task
                    Force, April 1999.
                                 Natural Resources Defense Council
                                                               10
David Wallinga, M.D.
E-97

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                   Endocrine Disrupter Screening


                   Mandated under both SDWA and FQPA
                   No validated screen as yet.
                   Modes-of-action detected by these screening
                   tests will suggest a heightened concern for
                   risks of exposures during developmental
                   periods.
                   Highly relevant to controversial modes of
                   action in endocrine-active organs: thyroid,
                   mammary gland, adrenal etc.
                                Natural Resources Defense Council
                                                              11
                   Protecting Children Can't Wait

               • Proposed Guidelines have been applied to at least 45
                 pesticides since August 1996.
               «> Draft Guidelines used to revise IRIS or create new IRIS files
                 for 15 chemicals from 1996 to 1998, including arsenic,
                 benzene, chromium IV and PCBs.
               o New or revised IRIS assessments for another 22 chemicals
                 anticipated in FY2000, including 1,3 Butadiene, cadmium,
                 chloroform, formaldehyde, and toxaphene.
               e New or revised IRIS assessments anticipated for another 27
                 chemicals in FY 2001, including acetaldehyde,
                 benzo(a)pyrene, and ethylene oxide.
                                Natural Resources Defense Council
                                                              12
David Wallinga, M.D.
                                        E-98

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                         Overheads from
Topic 4: Epidemiologic/Molecular Epidemiology Information to Address
                      Children's Cancer Risk
                         (Leslie Robison)
                              E-99

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Epidemiology/Molecular Information to
    Address Children's Cancer Risk

    •  Relatively Rare
    •  Unique from adult malignancies
    •  Increasingly recognized as biologically distinct
       subgroups
    •  Relative lack of etiologic information

IS THERE A NEED FORA NATIONAL INITIATIVE?
   National Network for Research
   on Cancer in Children

 A national registry of children with cancer for identifying
 environmental & other causes of childhood cancer
 To build upon the unique national clinical trials system for
 treating children with cancer
 To identify children at the time of their cancer diagnosis, allowing
 collection of tissue specimens
 To coordinate efforts with population-based cancer registries
 To support and facilitate scientific studies of the highest merit by
 the qualified investigators to study causes of cancer in children
                     E-101

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  Why a "National" Network to Study

  Causes of Cancer in Children ?


 The cancers of children differ from those in adults
 in their histology and in their biological
 characteristics

 8700 new cases diagnosed annually in children
 younger than 15 years of age, and the numbers
 of children with any given diagnosis is relatively
 small
  Why a "National" Network to Study

  Causes of Cancer in Children?

Within many tumor diagnoses are subtypes defined
by specific chromosomal changes:
 • these distinctive subtypes are likely to arise through
  different pathogenetic mechanisms
A National Network allows identification of sufficient
numbers  of cases to permit study of distinctive
biologically-defined categories of tumors defined by
specific alterations in tumor-associated genes
The National Network needs to have the capability of
defining tumors by their key biological characteristics
                   E-102

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      Estimated Numbers of Cancers
      in Children in U.S.
    Ewlng's sarcoma
     Osteosarcoma
           Wilms
     Neurobtastoma
     Acute myelold
       leukemia

    Acute Lymphoid
      Leukemia
                0   200  400  600  800  1000  1200 1400 1600  1800 2000 2200

                       Estimated Number of Cases in U.S. per Year
 Estimated Number of Cases of ALL Annually in
 U.S. by Molecular Subtype
    TCR and TAL1


  ABL-BCR: t(9;22)


  PBX1-E2A:t(1;19)


     MLL: t(11;v)


TEL-AML1: t(12;21)


     Hyperdiploid
                   50    100   150   200   250  300   350   400

                      Estimated Number of Cases in U.S. per Year
                          E-103

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Estimated Numbers of Brain Cancers
in Children in U.S.
        0   200  400  600  800  1000 1200 1400 1600 1800 2000

             Estimated Number of Cases in U.S. per Year
 Why a "National" Network to Study
 Causes of Cancer in Children?

i The causes of most cancers in children are not
 known.
i Known Risk Factors for Childhood Cancer
 explain only a small percentage of cases:
  • Prenatal diagnostic x-ray exposure
  • Postnatal therapeutic radiation or chemotherapy
  • Down syndrome, and other genetic diseases (e.g.,
   Bloom syndrome, neurofibromatosis, ataxia
   telangiectasia)
                  E-104

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 Factors with Inconsistent or Limited
 Evidence Linking to Childhood Cancer
Maternal and paternal
smoking prior to and during
pregnancy             :
Parental occupations and
occupational exposures
Diet
Electromagnetic fields
Indoor radon exposure
Vitamin K prophylaxis in
newborns
ii Parental and child
  exposure to pesticides
n Maternal alcohol
  consumption during
  pregnancy
•i In utero and postnatal
  infections
• Other environmental toxic
  exposures
 Why a "National" Network to Study
 Causes of Cancer in Children ?

Opportunities Justifying National Network
 • Advances in molecular characterization of
  tumors
 • Advances in exposure assessment
  methodology
 •Advances in understanding and evaluating for
  genetic susceptibility
                  E-105

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   Improved Methodologies/Technologies for
              Causation Research

• GIS technologies for hypothesis generation and
  correlation
• Sophisticated categorization of occupational
  categories relevant to specific exposures
• Exposure assessment (ability to detect minute
  quantities of substances in biological fluids and in the
  environment)
•i Identification of biological markers of exposure and
  susceptibility
•i Identification of potential genetic susceptibility factors
     Why a "National" Network to Study
     Causes of Cancer in Children?

   To Overcome Limitations of Previous
   Childhood Cancer Causation Studies
    •  Insufficient numbers to identify meaningful
      increases in risk
    •  Analyses combining diverse, biologically distinctive
      tumor types
    •  Inadequate/unreliable assessments of exposure
   Secondary benefits: Studying patterns of care,
   enhancing national surveillance capabilities
                      E-106

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Pediatric Clinical Trials Cooperative Groups

 m Children's Cancer Group and Pediatric
   Oncology Group represent over 200
   institutions throughout U.S. and Canada that
   are involved in the treatment of most children
   with cancer

 m Register approximately 94 percent of children
   under the age of 15 years diagnosed with
   cancer

 m Unifying into single Pediatric Clinical Trials
   Group:  The Children's Oncology Group
   CCG Member Institutions
   in North America and Australia
                      O Full Member
                      ° Affiliate Member
                                       CCG
                                       Beyer
                 E-107

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   Pediatric Oncology Group Institutions
   (Continental United States)
Childhood Cancer Epidemiological Studies
Conducted Through Cooperative Groups
 Osteosarcoma
 Heptatoblastoma
 Swing's Sarcoma
 AML
 Wilms' Tumor
 Retinoblastoma
 NHL
 Infant Leukemia
Twin Concordance
PNET and Astrocytoma
Hodgkin's Disease
ALL
Neuroblastoma
HIV- Malignancies
PNET/Medulloblastoma
Rhabdomyosarcoma
                   E-108

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   Opportunities Created by a Single
   Pediatric Clinical Trials  Group

 \ Most children with cancer in U.S. will be seen
  by COG member institutions
  Institutions will request patient/family
  participation in the Network at or near time of
  diagnosis
  Opportunity for collection of tissue specimens
  (e:g., tumor tissue, blood, buccal cells) at time
  of diagnosis
  Key Elements of National Network

i At time of diagnosis at GOG institution,
 permission requested to include the patient in the
 Network's registry of childhood cancer cases.
 • Family consent to be contacted to consider participation
   in future studies relating to identifying causes of
   childhood cancer.
 After permission is granted, information
 concerning the case is submitted to the COG
 Data Center
                  E-109

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   COG Registration/Consent Protocol
       'Level" of Registration
          COG Case Registration
\
Consent to Register with Identifiers
        Consent to Be Contacted
                              \
      National
      Network
    Registration/Consent Task Force

  • Registration/Consent Protocol
  • Informatics
  • Biological Specimens
  «> Collaboration with State and regional registries
  « Assess institutional practices and resources
  • Cancer registration consultants
  « Research infrastructure
                      E-110

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COG Registration/Consent Task Force
       Year 2000 Timeline
Registration/Consent Protocol
Informatics
Biological Specimens
Collaboration with State and regional registries
Assess institutional practices and resources
Cancer registration consultants
Research infrastructure
  Fall
Summer
Summer
 Spring
 Spring
 Spring
Summer
  Key Elements of National Network
i Serves as a resource for scientists wishing to
 conduct hypothesis-driven research studies
 relating to potential environmental and/or
 genetic causes of cancer in children.
 Network responsible for establishing Committee
 to review proposals to utilize the Network.
 Review based on:
 • the proposals' scientific soundness and merit, and
 • on inclusion of appropriate safeguards for
   participating patients/families
                  E-lll

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     PEDIATRIC CANCER SURVIVORS
  Precise Exposure
      Assessment

Defined Mechanisms
   Access to subjects

  Monitor Progression
                   Influence of primary
                   disease
                i  disease
Medical Exposure
	*-—-	1  Relevance of Mechanism
        I           of Action

  	1   Route of exposure
  Intermediate
                       Markers
                                      Range of exposure
                     Biomarkers of
                   Effect/Progression
                          T
   Well characterized  | Cancer Outcome |
        STUDY OF SECONDARY LEUKEMIA
          Alkylating Agents     Genetic susceptibility
         Medical Exposure [


Intermediate
Markers
           Biomarkers of
         Effect/Progression
                             Exposure markers


                             Intermediate markers
          Cancer Outcome |    Markersof effect

           T-MDS, AML
                          E-112

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  Overheads from
Workshop Summary
  (George Lucier)
        E-113

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         APPENDIX F
LIST OF BACKGROUND MATERIALS
  PROVIDED TO PARTICIPANTS
    PRIOR TO THE MEETING

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  Document entitled "Comparison of the effects of chemicals with combined perinatal and adult exposure vs. adult only exposure in
  carcinogenesis bioassays."


  Report of the 1996 FIFRA Scientific Advisory Panel meeting addressing "Comparison of the effects of chemicals with combined
  perinatal and adult exposure vs. adult only exposure in carcinogenesis bioassays."

  Document entitled "A proposed OPP policy on determining the need for in-utero/perinatal carcinogenicity testing on a pesticide."

  Report of the 1997 FIFRA Scientific Advisory Panel meeting addressing "A proposed OPP policy on determining the need for in-
  utero/perinatal carcinogenicity testing on a pesticide."

  Background paper on availability of toxicity testing data for assessing cancer risk.

 American Academy of Pediatrics, Committee on Environmental Health. Cancer. In: Handbook of Pediatric Environmental Health. Elk
 Grove Village, IL: American Academy of Pediatrics.

 Colt, J.S., and A. Blair. 1998. Parental  occupational exposures and risk of childhood cancer. Environmental Health Perspectives
  106(Supplement 3):909-925.


 Legler, J.M., L.A.G. Ries, M.A. Smith, J.L. Warren, E.F. Heineman, R.S. Kaplan, and M.S. Linet. 1999. Brain and other central
 nervous system cancers: Recent trends  in incidence and mortality. Journal of the National Cancer Institute 91(16): 1,382-1,390.

 Linet, M.S., L.A.G. Ries, M.A. Smith, R.E. Tarone, and S.S. Devesa. 1999. Cancer surveillance series:  Recent trends in childhood
 cancer incidence and mortality in the United States. Journal of the National Cancer Institute 91(12): 1,051-1,058.

 National Research Council. 1993. Executive summary. In: Pesticides in the diets of infants and children. Washington, DC: National
 Academy Press, pp. 1-12.


 Perera, P.P. 1997. Environment and cancer: Who are susceptible? Science 278:1,068-1,073.

 Perera, P.P., R.M. Whyatt, W. Jedrychowski, R. Rauh, D. Manchester, R.M. Santella, and R. Ottman. 1998. Recent developments in
 molecular epidemiology: A study of the effects of environmental polycyclic aromatic hydrocarbons on birth outcomes in Poland.
 American Journal of Epidemiology  147(3):309-314.


 Perera, F.P., W. Jedrychowski, V. Rauh, and R.M. Whyatt. 1999. Molecular epidemiologic research on the effects of environmental
 pollutants on the fetus. Environmental Health Perspectives 107(Supplement 3):451-460.

 Ries, L.A.G., M.A. Smith, J.G. Gurney, M. Linet, T. Tamra, J.L. Young, and G.R. Bunin (eds). 1999. Cancer incidence and survival
 among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program NIH 99-4649
 Bethesda, MD.


 Tang, D.,  D. Warburton, S.R. Tannenbaum, P. Skipper, R.M. Santella, G.S. Cereijido, F.G. Crawford, and F.P. Perera. 1999.
 Molecular and genetic damage from environmental tobacco smoke in young children. Cancer Epidemiology Biomarkers &
 Prevention 8:427-431.


 U.S. Environmental Protection Agency. 1999. Guidelines for carcinogenic risk assessment (review draft). Washington, DC.

Zahm, S.H., and M.H.  Ward. 1998. Pesticides and childhood cancer. Environmental Health Perspectives 106(Supplement 3):893-908.
                                                          F-3

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United States
Environmental Protection Agency/ORD
National Center for
   Environmental Assessment
Washington, D.C. 20460
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