ABSTRACT
It is now recognized that a critical issue in extrapolating from animal studies to humans is the definition of which human or group of humans is concerned. Since there is a wide range of differential sensitivities to toxic substances, it is important that investigators identify the most susceptible or high-risk groups in the population, because these are the individuals who will first experience morbidity and mortality as a result of exposure to toxic/ carcinogenic agents. If the high-risk segment of the population can be protected, then the entire population is likewise assured protection. In my earlier book, Pollutants and High Risk Groups (1978), factors affecting enhanced susceptibility were identified as developmental/aging processes, genetic conditions, nutritional status, preexisting diseases, and life-style considerations. Table 7-1 provides a list of groups at potentially enhanced risk to environmental pollutants. This chapter will address in detail a selected number of these high-risk conditions, including an evaluation of the utility of animal models to accurately predict the responses of humans with these diseases. Addressing each potential animal model for a human high-risk group in detail would be a valuable undertaking and would constitute a separate volume of its own. The Identification and Quantification of High-Risk Groups
High-Risk Groups
Estimated Number of Individuals in the United States Affected
Pollutant(s) to Which High-Risk Group Is (May Be) At Increased Risk
Developmental Processes
Immature enzyme detoxification systems
Embryos, fetuses, and neonates to the age of approximately 3-6 months
Pesticides
PCBs
Immature immune system
Infants and children do not reach adult levels of IgA until the age of 10-12
Respiratory irritants
Deficient immune system as a function of age
Progressive degeneration after adolescence
Carcinogens
Respiratory irritants
Adolescents, especially carriers of porphyria genes
See population frequency for porphyrias
Chloroquine
Hexachlorobenzene
Lead
Variety of medical drugs
Differential absorption of pollutants as a function of age
Infants and young children
Barium
Lead
Radium
Strontium
Retention of pollutants as a function of age
Individuals above the age of 50
Fluoride
Pregnancy
Approximately 20 females per 50,000 females per year in the United States
Carbon monoxide
Insecticides
Lead
Circadian rhythms, including phase shifts
All people have certain periods of the day when they are more susceptible to challenge
Carcinogens
Probably most other pollutants
Infant stomach acidity
Infants
Nitrate
291Albinism
Genetic Factors
Tyrosinase positive
1 per 14,000 blacks; 1 per 60,000 whites; very high frequency in American Indians;
Ultraviolet radiation
Tyrosinase negative
1 per 34,000-36,000 blacks and whites; 1 per 10,00015,000 in Ireland
Catalase deficiency
Hypocatalasemia
5,000,000 heterozygotes
Ozone
Acatalasemia
16,000 homozygotes
Radiation
Cholinesterase variants
Highly sensitive homozygous and heterozygous individuals of European ancestry have a combined frequency of about 1 per 1250
Moderately sensitive genotypic variants of European ancestry have a frequency of 1 per 15,000
Anticholinesterase Insecticides
Crigler-Najjar syndrome
Few individuals live to adulthood
PCBs
Cystic fibrosis
8,000,000 heterozygous for cystic fibrosis 100,000 homozygous for cystic fibrosis
Ozone
Respiratory irritants
Most common among whites of European ancestry
Cystinosis
Most common among whites of European ancestry; unknown frequency
Cadmium
Lead
Mercury
Uranium
Cystinuria
1 per 200-250 individuals, although asymptomatic, are affected;
Cadmium Lead
1 per 20,000-100,000 are homozygous
Mercury Uranium
Glucose-6-phosphate dehydrogenase deficiency
1,600,000 American black males (11-13%) Mediterranean Jews 11.0%; Greeks 1-2%; Sardinians 1-8%
Carbon monoxide
Ozone
Radiation
Glutathione deficiency
Only a few cases have been reported
Lead Ozone
292Glutathione peroxidase deficiency
Partial deficiency in some neonates; only a few adult cases reported
Lead
Ozone
Glutathione reductase deficiency
Unknown, but thought to be rare
Lead
Ozone
Gilbert’s syndrome
6% of the normal, healthy adult population
PCBs
Immunoglobin A deficiency
500,000 homozygotes
Respiratory irritants
Immunologic hypersensitivity
2% of some worker populations
Isocyanates
Inducibility of aryl hydrocarbon hydroxylase
Approximately 45% of the general population are at high risk; 9% of the 45% are at very high risk
Polycyclic aromatic hydrocarbons
Leber’s optic atrophy
Thought to be rare
Cyanide
Methemoglobin reductase deficiency
Found in many ethnic groups; gene frequency is uncertain, but thought to be rare; most infants experience a temporary deficiency
Nitrates
Ozone
Vanadium
Phenylketonuria
1 per 80 in the United States is a carrier; 1 per 25,000 has the disease
Ultraviolet light
Porphyrias
1.5 per 100,000 in Sweden, Denmark, Ireland, and West Australia; 3 per 1000 in South African whites; rare in blacks
Chloroquine
Hexachlorobenzene
Lead
Various drugs including barbiturates, sulfonamides, and others
293Serum α,-antitrypsin deficiency
Approximately 4.0-9.0% individuals of Northern European descent are heterozygotes
Approximately 160,000 homozygotes based on frequency found in Norway and Sweden
Respiratory irritants
Smoking
Sickle cell
Trait (heterozygote)
Anemia (homozygote)
7-13% of American blacks—heterozygotes
Homozygotic condition highly fatal
Aromatic amino and nitro compounds
Carbon monoxide Cyanide
Sulfite oxidase
Unknown
Sulfur dioxide, sulfite
Thalassemia (Cooley’s anemia)
Homozygous condition highly fatal; heterozygote frequency high (0.1-8.0%) in certain people of Italian, Greek, Syrian, and black origin
Lead
Organic chemicals such as
benzene and its
derivatives Ozone
Tyrosinemia
Frequency in general population unknown; frequency of heterozygous carriers in the Chicoutimi region of Northern Quebec is 1 carrier for every 20-31 people
Cadmium
Lead
Mercury
Uranium
Wilson’s disease
400,000 heterozygotes; 200 homozygotes—most frequent among Jews of Eastern European ancestry and non-Jews from the Mediterranean regions, especially Sicily
Lead
Vanadium
Xeroderma pigmentosum
Occurs in all racial groups with a frequency of 1/250,000; the heterozygote has a frequency of 2-4/1000
Certain hydrocarbon carcinogens
Ultraviolet radiation
Nutritional Deficiencies
Vitamin A
25% of children between 7 and 12 have lower than recommended dietary allowance (RDA); slightly higher percentage among the lower-income groups
Carcinogens
DDT
PCBs
294Vitamin C
10-30% of infants, children, and adults of low-income groups receive less than the RDA
Arsenic
Cadmium
Carbon monoxide
Chromium
DDT
Dieldrin
Lead
Mercury
Nitrites
Nitrates
Ozone
Vitamin E
7% of the general population are “physiologically deficient”
Cadmium
Lead
Ozone
Calcium
65% of children between the ages of 2 and 3 receive less than the RDA
Cadmium
Lead
Iron
98% of children between the ages of 2 and 3 receive less than the RDA
Cadmium
Lead
Manganese
Magnesium
Most U.S. males have a partial deficiency
Cadmium
Phosphorus
Deficiency in people with various kidney diseases
Lead
Selenium
Unknown deficiency, thought to be rare
Cadmium
Mercury
Ozone
295Zinc
Deficiency present in association with various diseases, but not thought to be widespread
Cadmium
Riboflavin
30% of women and 10% of men aged 30-60 ingest less than two-thirds of the RDA
Hydrocarbon carcinogens
Lead
Ozone
Dietary protein
10% of women and 5% of men aged 30-60 ingest less than two-thirds of the RDA for protein
DDT
Methionine
Unknown, but thought to be more common in individuals following certain vegetarian diets
DDT
Diseases
Kidney disease
Relates to genetic diseases (see cystinosis, cystinuria, tyrosinemia), bacterial and virus infections, and hypertensive disease
Lead
Other heavy metals
Excessive sodium in diet
Liver disease
Relates to genetic diseases (Gilbert’s syndrome) and virus infections
Carbon tetrachloride
DDT and other insecticides
PCBs
Asthmatic diseases
4,000,000-10,000,000 of the general population
Respiratory irritants:
Nitrogen dioxide
Ozone
Sulfates
Sulfur dioxide
Chronic respiratory disease
6,000,000-10,000,000 of the general population
Respiratory irritants:
Nitrogen dioxide
Ozone
Sulfates
Sulfur dioxide
296Heart disease
15,000,000 of the general population
Respiratory pollutants:
Carbon monoxide
Ozone
Sulfur dioxide
Excessive sodium in diet
Behavioral Activities
Smoking
Widespread
Cadmium Lead
Polycyclic aromatic hydrocarbons
Radium-226
Alcohol consumption
Widespread
Lead
Pesticides
PCBs
Drug taking
Widespread
Pesticides
PCBs
Source: Calabrese (1978), Pollutants and High Risk Groups, Wiley-Interscience, New York, p. 187.