chapter  7
102 Pages

Animal Models for Selected High-Risk Groups

ByEdward J. Calabrese

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.