Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Age-specific Carcinogenesis: Environmental Exposure and Susceptibility
Richard D. Thomas
International Center for Environment and Health, Arlington, Virginia
Abstract
Environmental exposures in children may occur through many routes, including
diet, air, and the ingestion of various nonfood items such as medications
and household materials. This article focuses on dietary exposure, but it
does highlight the importance of considering other routes of exposure when
assessing exposure in children. It presents many of the findings in the
two recent reports, Pesticides in the Diets of Infants and Children and
Science and Judgment in Risk Assessment of the National Academy of Sciences
(NAS)/National Research Council (NRC). Diet is an important source of exposure
for children to potential carcinogens. The trace quantities of chemicals
present on or in foodstuffs are termed residues. In addition, there are
substances that children may be exposed to in air and water that should
be considered in a total exposure analysis. To minimize exposure of the
general population to chemical residues in food, water, and air, the U.S.
government has instituted regulatory controls. These are intended to limit
exposures to residues while ensuring an abundant and nutritious food supply,
and safe drinking water and air. The legislative framework for these controls
was established by the Congress through various local and state laws and
such federal laws as the Insecticide, Fungicide, and Rodenticide Act (FIFRA),
the Federal Food, Drug, and Cosmetic Act (FFDCA), the Safe Drinking Water
Act (SDWA), and the Clean Air Act (CAA). This article summarizes current
approaches to assessing exposure and susceptibility in children. -- Environ
Health Perspect 103(Suppl 6):45-48 (1995)
Key words: infants and children, pesticides, risk assessment,
dietary exposure, carcinogenesis, chemical residues, pesticide residues,
toxicity testing, exposure assessment
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1993 in Washington, DC.
Address correspondence to Richard D. Thomas, Director,
International Center for Environment and Health, 1901 North Fort Myer Drive,
Suite 400, Arlington, VA 22209. Telephone (703) 527-6500. Fax (703) 243-0013.
Introduction
Environmental exposures in children may occur through many routes, including
diet, air, and the ingestion of various nonfood items such as medications
and household materials. This article focuses on dietary exposure, but it
also highlights the importance of considering other routes of exposure when
assessing exposure in children. It presents many of the findings in
two recent reports, Pesticides in the Diets of Infants and Children (1)
and Science and Judgment in Risk Assessment (2). Diet is an important
source of exposure for children to potential carcinogens. The trace quantities
of chemicals present on or in foodstuffs are termed residues. In addition,
there are substances that children may be exposed to in air and water that
should be considered in a total exposure analysis.
To minimize exposure of the general population to chemical residues in
food, water, and air, the U.S. government has instituted regulatory controls.
These are intended to limit exposures while ensuring an abundant and nutritious
food supply, and safe drinking water and air. The legislative framework
for these controls was established by Congress through various local and
state laws and such federal laws as the Insecticide, Fungicide, and Rodenticide
Act (FIFRA), the Federal Food, Drug, and Cosmetic Act (FFDCA), the Safe
Drinking Water Act (SDWA), and the Clean Air Act (CAA).
Several different "acceptable concentrations" are established
for chemicals in the environment. For example in the case of pesticides,
tolerances constitute the single most important mechanism by which the U.S.
Environmental Protection Agency (U.S. EPA) limits levels of pesticide residues
in foods. A tolerance is defined as the legal limit of a pesticide
residue allowed in or on a raw agricultural commodity and, in appropriate
cases, on processed foods. A tolerance must be established for any pesticide
used on any food crop. Tolerances are not based primarily on health considerations
and have in the past not addressed the unique characteristics of infants
and children.
The exposure of infants and children and their susceptibility to harm
from ingesting pesticide residues differs from that of adults (3,4).
Since the current regulatory system does not specifically consider
infants and children, it does not examine the wide range of pesticide exposure
patterns that appear to exist within the U.S. population. It looks only
at the average exposure of the entire population. As a consequence, variations
in dietary exposure to pesticides and health risks related to age and such
other factors as geographic region and ethnicity are not addressed in current
regulatory practice. In addition, humans vary substantially in their inherent
susceptibility to carcinogenesis (4,5). If each stage in carcinogenesis
is examined (e.g., carcinogen uptake and metabolism, DNA damage, DNA repair
and misrepair, cell proliferation, tumor progression, and metastasis), there
may be substantial variability between humans (6,7). Furthermore,
some individuals may have determinants (e.g., germ-line mutations in tumor-suppressor
genes) that substantially enhance their susceptibility to cancer-causing
chemicals (8-13).
Concern about the potential vulnerability of infants and children to
dietary pesticides led the U.S. Congress in 1988 to request that the National
Academy of Sciences (NAS)/National Research Council (NRC) examine this issue
(1).
Age-related Variation in Susceptibility and Toxicity
A fundamental maxim of pediatric medicine is that children are not "little
adults." Profound differences exist between children and adults. Infants
and children are growing and developing (14-22). Their metabolic
rates are more rapid than those of adults (23-32). There are differences
in their abilities to activate, detoxify, and excrete xenobiotic compounds.
All these differences can affect the toxicity of pesticides or other chemical
substances in infants and children, and for these reasons the toxicity of
pesticides is frequently different in children than in adults (31-35).
Children may be more sensitive or less sensitive than adults, depending
on the pesticide to which they are exposed. Moreover, because these processes
can change rapidly and can counteract one another, there is no simple way
to predict the kinetics and sensitivity to chemical compounds in infants
and children from data derived entirely from adult humans or from toxicity
testing in adult or adolescent animals (1).
The NRC found both qualitative and quantitative differences in toxicity
of pesticides and other chemicals between children and adults. Qualitative
differences in toxicity are the consequence of exposures during special
windows of vulnerability--brief periods early in development when exposure
to a toxicant can permanently alter the structure or function of an organ
system (14,36,37). Classic examples include chloramphenicol exposure
of newborns and vascular collapse (gray baby syndrome (26)), tetracycline
and dysplasia of the dental enamel, and lead and altered neurologic development
(28).
Quantitative differences in toxicity between children and adults are
due in part to age-related differences in absorption, metabolism, detoxification,
and excretion of xenobiotic compounds, that is, to differences in both pharmacokinetic
and pharmacodynamic processes. Differences in size, immaturity of biochemical
and physiological functions in major body systems, and variation in body
composition (water, fat, protein, and mineral content) all can influence
the extent of toxicity (19,20,38). Because newborns are the group
most different anatomically and physiologically from adults, they may exhibit
the most pronounced quantitative differences in sensitivity to chemicals
(3,39,40).
The NRC concluded that the mechanism of action of a toxicant--how it
causes harm--is generally similar in most species and across age and developmental
stages within species (9). For example, if a substance is cytotoxic
in adults, it is usually also cytotoxic in immature individuals.
Lack of data on chemical toxicity in developing organisms was a recurrent
problem encountered by the NRC. In particular, little work has been done
to identify effects that develop after a long latent period or to investigate
the effects of chemical exposure on chronic neurotoxic, immunotoxic, or
endocrine responses in infants and children. We therefore had to rely mostly
on incomplete information derived from studies in mature animals.
The NRC reviewed current U.S. EPA requirements for toxicity testing by
chemical manufacturers, as well as testing modifications proposed by
the agency. In general, we found that current and past studies conducted
by chemical manufacturers are designed primarily to assess 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 chemicals
in neonates and adolescent animals or the effects of exposure during early
developmental stages and their sequelae in later life.
Age-related Differences in Exposure
Estimation of the exposures of infants and children to chemical residues
requires information on dietary composition, residue concentrations in and
on the food and water consumed, and other routes of exposure. The NRC found
that infants and children differ both qualitatively and quantitatively from
adults in their exposure to chemical residues in foods (1). Children
consume more calories of food per unit of body weight than do adults. But
at the same time, infants and children consume far fewer types of foods
than do adults. Thus, infants and young children may consume much more of
certain foods, especially processed foods, than do adults. And water consumption,
both as drinking water and as a food component, is very different between
children and adults. Differences in exposure were generally a more important
source of differences in risk than were age-related differences in toxicologic
vulnerability. It should be noted that infants and young children consume
large quantities of processed foods, such as fruit juices, baby food, milk,
and infant formula. The younger the child, the less diverse are the foods
that are consumed.
The high levels of consumption within a particular age group are especially
relevant when considering foods that might contain residues capable of causing
acute toxic effects. Also, geographic, ethnic, and other differences may
be overlooked. To overcome the problems inherent in the current reliance
on "average" exposures, we used the technique of statistical convolution
(i.e., combining various databases) to merge distributions of food consumption
with distributions of residue concentrations. This approach permits examination
of the full range of pesticide exposures in the pediatric population of
the United States.
New Approaches to Risk Assessment for Infants and Children
To properly characterize risk to infants and children from pesticide
residues in the diet, information is required on food consumption patterns
of infants and children, concentrations of pesticide residues in foods consumed
by infants and children, and toxic effects of pesticides, especially effects
that may be unique to infants and children. If suitable data on these three
items are available, risk assessment methods based on the technique of statistical
convolution can be used to estimate the likelihood that infants and children
who experience specific exposure patterns may be at risk. To characterize
potential risks to infants and children in this fashion, we utilized data
on distributions of pesticide exposure that, in turn, were based on distributions
of food consumption merged with data on the distribution of pesticide residue
concentrations. The NRC found that age-related differences in exposure patterns
for 1- to 5-year-old children were most accurately illuminated by using
1-year age groupings of data on children's food consumption (1).
Exposure estimates should be constructed differently depending on whether
acute or chronic effects are of concern. Average daily ingestion of pesticide
residues is an appropriate measure of exposure for assessing the risk of
chronic toxicity. However, actual individual daily ingestion is more appropriate
for assessing acute toxicity. Because chronic toxicity is often related
to long-term average exposure, the average daily dietary exposure to pesticide
residues may be used as the basis for risk assessment when the potential
for delayed, irreversible chronic toxic effects exists. Because acute toxicity
is more often mediated by peak exposures occurring within a short period
(e.g., over the course of a day or even during a single eating occasion),
individual daily intakes are of interest. Examining the distribution of
individual daily intakes within the population of interest reflects
day-to-day variation in pesticide ingestion both for specific individuals
and among individuals.
Compared to late-in-life exposures, exposures to pesticides early in
life can lead to a greater risk of chronic effects that are expressed only
after long latency periods have elapsed. Such effects include cancer, neurodevelopmental
impairment, and immune dysfunction. The NRC developed new risk assessment
methods to examine this issue (1,2).
Although some risk assessment methods take into account changes in exposure
with age, these models are not universally applied in practice. The NRC
explored the use of newer risk assessment methods that allow for changes
in exposure and susceptibility with age (41-47). However, we found
that sufficient data are not currently available to permit wide application
of these methods.
Conclusions and Recommendations
Estimates of expected total exposure to pesticide residues should reflect
the unique characteristics of the diets of infants and children and should
account also for all dietary and nondietary intake of pesticides and other
chemical substances. Exposure estimates should recognize that pesticide
residues may be present on more than one food commodity consumed by infants
and children and that more than one pesticide may be present on one food
sample. Finally, determinations of safe levels of exposure should take into
consideration the physiologic factors that can place infants and children
at greater risk of harm than adults.
Toxicity Testing
The NRC believes it is essential to develop toxicity testing procedures
that specifically evaluate the vulnerability of infants and children.
Testing must be performed during the developmental period in appropriate
animal models and the adverse effects that may become evident must be monitored
over a lifetime. Of particular importance are tests for neurotoxicity and
toxicity to the developing immune and reproductive systems.
Exposure Assessment
The available data indicate that infants and children consume much more
of certain foods on a body-weight basis than do adults. Because higher exposures
can lead to higher risks, it is important to have accurate data on food
and water consumption patterns for infants and children. To maximize the
utility of pesticide residue data collected by various laboratories, the
NRC recommends the use of comparable analytic methods and standardized reporting
procedures and the establishment of a computerized data base to collate
data on pesticide residues generated by different laboratories. More complete
information is needed on the effects of food processing on levels of pesticides--both
the parent compound and its metabolite--in specific food-chemical combinations
potentially present in the diets of infants and children.
Risk Assessment
All exposures to pesticides--dietary and nondietary--need to be considered
when evaluating the potential risks to infants and children. Nondietary
environmental sources of exposure include air, dirt, indoor surfaces, lawns,
and pets.
* Estimates of total dietary exposure should be refined to consider
intake of multiple pesticides with a common toxic effect. Converting residues
for each pesticide with a common mechanism of action to toxicity equivalence
factors for one of the compounds would provide one approach to estimating
total residue levels in toxicologically equivalent units.
* Consumption of pesticide residues in water is an important potential
route of exposure. Risk assessment should include estimates of exposure
to pesticides in drinking water and in water as a component of processed
foods.
Given adequate data on food consumption and residues, the NRC recommends
the use of probability distributions rather than single-point data to characterize
the likelihood of exposure to different concentrations of pesticide residues.
The distribution of average daily exposure of individuals in the population
of interest is most relevant for use in chronic toxicity risk assessment,
and the distribution of individual daily intakes is recommended for evaluating
acute toxicity.
The NRC identified important differences in susceptibility to the
toxic effects of pesticides and exposure to pesticides in the diet with
age. For carcinogenic effects, the NRC proposed new methods of cancer risk
assessment designed to take such differences into account. Preliminary analyses
conducted by the NRC suggest that consideration of such differences can
lead to lifetime estimates of cancer risk that can be higher or lower than
estimates derived with methods based on constant exposure. Currently, most
long-term laboratory studies of carcinogenesis and other chronic end points
are based on protocols in which the level of exposure is held constant during
the course of the study. To facilitate the application of risk assessment
methods that allow for changes in exposure and susceptibility with age,
it would be desirable to develop bioassay protocols that provide direct
information on the relative contribution of exposures at different ages
to lifetime risks. Although we do consider it necessary to develop special
bioassay protocols for mandatory application in the regulation of pesticides,
it would be useful to design special studies to provide information on the
relative effects of exposures at different ages on lifetime cancer and other
risks with selected chemical carcinogens.
In summary, better data on dietary exposure to chemical residues should
be combined with improved information on the potentially harmful effects
of chemicals on infants and children. Risk assessment methods that enhance
the ability to estimate the magnitude of these effects should be developed,
along with appropriate toxicological tests for perinatal and childhood toxicity.
REFERENCES
1. National Research Council. Pesticides in the Diets of
Infants and Children. Washington:National Academy of Sciences, 1993.
2. Judgment in Risk Assessment. Washington:National Academy
of Sciences, 1994.
3. Calabrese EJ. Age and Susceptibility in Toxic Substances.
New York:Wiley-Interscience Publications, 1986.
4. Anisimov VN. Role of age in host sensitivity to carcinogens.
International Agency for Research on Cancer. Sci Publ 51:99-112 (1983).
5. Anisimov VN. Modifying effects of aging on N-methyl-N-nitrosources-induced
carcinogenesis in female rats. Exp Pathol 19:81-90 (1981).
6. Cohen SM, Ellwein LB. Genetic errors, cell proliferation,
and carcinogenesis. Cancer Res 51:6493-6505 (1991).
7. Cohen SM, Purtilo DT, Ellwein LB. Pivotal role of increased
cell proliferation in human carcinogenesis. Mod Pathol 4:371-382 (1991).
8. Hildreth NG, Shore RE, Dvoretsky PM. Risk of breast
cancer after irradiation of the thymus in infancy. New Engl J Med 321:1281-1284
(1989).
9. Miller AB, Howe GR, Sherman GJ, Lindsay JP, Yaffe MJ,
Dinner PJ, Risch HA, Preston DL. Mortality from breast cancer after irradiation
during fluoroscopic examinations in patients being treated for tuberculosis.
N Engl J Med 321:1285-1289 (1989).
10. Norman JE Jr. Breast cancer in women irradiated early
in life. In: Banbury Report 11: Environmental Factors in Human Growth and
Development (Hunt VR, Smith MK, Worth D eds). New York:Cold Spring Harbor
Laboratory, 1982;433-450.
11. Rajewski MP. Tumorigenesis by exogenous carcinogens:
role of target-cell poliferation and state of differentiation (development).
In: Age-Related Factors in Carcinogenesis, Symposium Proceedings, International
Agency for Research on Cancer and N.N. Petrov Research Institute of Oncology,
IARC Scientific Publ No 58 (Likhachev A, Anisomov V, Montanaro R, eds).
Lyon:International Agency for Research on Cancer, 1985;215-224.
12. Singh SM, Toles JF, Reaume J. Genotype- and age-associated
in vivo cytogenetic alterations following mutagenic exposures in
mice. Can J Genet Cytol 28:286-293 (1986).
13. Weinstein LB. Mitogenesis is only one factor in carcinogenesis.
Science 251:387-388 (1991).
14. Altman PL, Dittmer DS, eds. Growth--Including Reproduction
and Morphological Development. Washington:Federation of American Societies
for Experimental Biology, 1962.
15. Coppoletta JM, Wolbach SB. Body length and organ weights
of infants and children. Am J Pathol 9:55-59 (1933).
16. Dickerson JWT. Changes in the composition of the human
femur during growth. Biochem J 82:56-61 (1962).
17. Dickerson JWT, Widdowson EM. Chemical changes in skeletal
muscle during development. Biochem J 74:247-257 (1960).
18. Fomon SJ. Body composition of the infant. Part 1: The
male reference infant. In: Human Development (Falkner F, ed). Philadelphia:WB
Saunders, 1966;239-246.
19. Forbes GB. Changes in body water and electrolyte during
growth and development. In: Body Composition in Animals and Man, Proceedings
of a Symposium, 4-6 May 1987, Columbia, Missouri. Publ 1958. Washington:National
Academy of Sciences, 1968;80-86.
20. Forbes GB. Body composition in adolescence. In: Human
Growth, Vol 2. Postnatal Growth (Falkner F, Tanner JM, eds). New York:Plenum
Press, 1978;239-272.
21. Kariberg J. On the construction of the infancy-childhood-
puberty growth standard. Acta Paediatr Scand Suppl 356:26-37 (1989).
22. Owen GM, Brozek J. Influence of age, sex, and
nutrition on body composition during childhood and adolescence. In: Human
Development (Falkner F ed). Philadelphia:Saunders, 1966;222-238.
23. Alvares AP, Kapelner S, Sassa S, Kappas A. Drug metabolism
in normal children, lead-poisoned children, and normal adults. Clin Pharmacol
Ther 17:179-183 (1975).
24. Altman PL, Dittmer DS, eds. Chemical composition of
nervous tissue. In: Biology Data Book, 2nd ed, Vol 2. Bethesda, MD:Federation
of American Societies for Experimental Biology, 1973;1206-1230.
25. Csaba G, Dobozy O. The sesitivity of sugar receptors:
analysis in adult animals of influences exerted at neonatal age. Endokrinologie
69:227-232 (1977).
26. Fleisch JH. Age-related changes in the sensitivity
of blood vessels to drugs. Pharmacol Ther 8:477-487 (1980).
27. Kleinman LI. The effect of lead on the maturing kidney.
In: Banbury Report 11: Environmental Factors in Human Growth and Development
(Hunt VR, Smith MK, Worth D, eds). New York:Cold Spring Harbor Laboratory,
1982;153-171.
28. Tyan ML. Age-related increase in erythrocyte oxidant
sensitivity. Mech Ageing Dev 20:25-32 (1982).
29. Widdowson EM. Biological implications of body composition.
In: Body Composition in Animals and Man, Symposium Proceedings, Publ 1598.
Washington:National Academy of Sciences, 1968;71-79.
30. Widdowson EM, Dickerson JWT. Chemical composition of
the body. In: Mineral Metabolism: An Advanced Treatise (Comar CL, Bronner
F, eds). New York:Academic Press, 1964;1-247.
31. Kalland T. Long-term effects on the immune system of
an early life exposure to diethylstilbestrol. In: Banbury Report 11: Environmental
Factors in Human Growth and Development (HuntVR, Smith MK, Worth D, eds).
New York:Cold Spring Harbor Laboratory, 1982;217-241.
32. Widdowson EM, Dickerson JWT. The effect of growth and
function on the chemical composition of soft tissues. Biochem J 77:30-43
(1960).
33. Hudson RH, Tucker RK, Haegele MA. Effect of age on
sensitivity: acute oral toxicity of 14 pesticides to mallard ducks of several
ages. Toxicol Appl Pharmacol 22:556-561 (1972).
34. Drew RT, Boorman GA, Haseman JK, McConnell EE, Busey
WM, Moore JA. The effect of age and exposure duration on cancer induction
by a known carcinogen in rats, mice, and hamsters. Toxicol Appl Pharmacol
68:120-130 (1983).
35. Finhorn L. Oncodevelopmental biology and medicine.
J Int Soc Oncodevel Biol Med 4:219-229 (1982).
36. Vesell ES. Dynamically interacting genetic and environmental
factors that affect the response of developing individuals to toxicants.
In: Banbury Report 11: Environmental Factors in Human Growth and Development
(Hunt VR, Smith MK, Worth D, eds). New York:Cold Spring Harbor Laboratory,
1982;107-124.
37. Swenberg JA, Fedtke N, Fishbien L. Age-related differences
in DNA adduct formation and carcinogenesis of vinyl chloride in rats. In:
Similarities and Differences Between Children and Adults (Guzelian PS, Henry
CJ, Olin SS, eds). Washington: ILSI Press, 1992;163-171.
38. FASEB. Blood and other body fluids. In: Biological
Handbooks: Biology Data Book, 2nd ed. Bethesda, MD: Federation of American
Societies for Experimental Biology, 1974;1751-2041.
39. Himwich WA. Problems in interpreting neurochemical
changes occurring in developing and aging animals. Prog Brain Res 40:13-23
(1973).
40. Rodier PM. Chronology of neuron development: animal
studies and their clinical implications. Dev Med Child Neurol 22:525-545
(1980).
41. Moolgavkar SH. Biologically motivated two-stage model
for cancer risk assessment. Toxicol Lett 43(1-3):139-150 (1988).
42. Moolgavkar SH, Venzon DJ. Two-event models for carcinogenesis:
incidence curves for childhood and adult tumors. Math Biosci 47:55-77 (1979).
43. Moolgavkar SH, Knudson AG. Mutation and cancer: a model
for human carcinogenesis. J Natl Cancer Inst 66(6):1037-1052 (1981).
44. Moolgavkar SH, Luebeck G. Two-event model for carcinogenesis:
biological, mathematical, and statistical considerations. Risk Anal 10:323-341
(1990).
45. Moolgavkar SH, Dewanji A, Venzon DJ. A stochastic two-stage
model for cancer risk assessment. I. The hazard function and the probability
of tumor. Risk Anal 8:383-392 (1988).
46. Moolgavkar SH, Luebeck EG, de Gunst, M, Port RE, Schwarz
M. Quantitative analysis of enzyme-altered foci in rat hepatocarcinogenesis
experiments I: Single agent regimen. Carcinogenesis 11:1271-1278 (1990).
47. Moolgavkar SH, Cross FT, Luebeck G, Dagle GE. A two-mutation
model for radon-induced lung tumors in rats. Radiat Res (121):28-37 (1990).
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