E. Developmental and Reproductive Effects

The EPA’s Office of Prevention, Pesticides and Toxic Substances (OPPTS) also

developed harmonized test guidelines that provide guidance on developmental toxicity and reproductive toxicity testing in animals. In addition, the guidelines are

designed to ensure that studies are uniformly performed and that information concerning the developmental or reproductive effects of exposure are adequately

reported. The guidance includes appropriate methodology, choice of species, endpoints to be examined, and interpretation of the results.

The harmonized developmental guidelines consider important aspects of developmental toxicity such as preliminary toxicity screening, inhalation toxicity testing,

and prenatal toxicity. The developmental guidelines also discuss the importance of

determining whether developmental toxicity, either reversible or irreversible, has

occurred and if it is unrelated to maternal toxicity. The focus of the harmonized

reproductive and fertility guidelines is on the design and conduct of a two-generation

reproduction study.

The potential developmental and reproductive effects of air pollution can be

assessed in epidemiologic studies. For instance, as part of the Teplice Program to

investigate the impact of air pollution on the health of the population in the district

of Teplice, Czech Republic, low birth weight, congenital malformations, premature

births, and fetal loss were examined in a prospective cohort design (Sram et al.

1996). For the reproductive portion of the study, a comparison of reproductive health

and semen quality outcomes in males living in Teplice with those of males living

in another area was performed.



III. HAZARDS OF SPECIFIC INDOOR AIR CONTAMINANTS

A diversity of pollutants has been detected in indoor air environments. Table 1

in Chapter 1 summarizes the primary indoor air pollutants. This section reviews the

health hazards that have been attributed to select indoor air pollutants, specifically,

particulates, chemicals including pesticides, volatile organics, combustion products,

tobacco smoke, and biological contaminants. Since there are extensive reviews on

some indoor air pollutants such as lead and radon, these will not be discussed in

any detail.

A. Particulates

The adverse health hazards of ambient levels of particulate matter have been

known for quite some time (Dockery and Pope 1994). In particular, increased

morbidity and mortality associated with acute episodes of air pollution during the

1930s, 1940s, and 1950s in Meuse Valley, Belgium, Donora, Pennsylvania, and

London, England are well documented, although the adverse effects cannot be solely

attributed to particulate matter. Other effects attributed to acute exposure to particulate matter are asthma, lung function changes, cough, sore throat, chest discomfort,

sinusitis, and nasal congestion. Epidemiological studies suggest chronic respiratory



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diseases and symptoms, and increased mortality following long-term exposure to

respirable particulate air pollution (Pope et al. 1995).

Early investigators quickly recognized that particulate matter is also an indoor

air pollutant. Moreover, concentrations of indoor particulate matter can be quite

different from outdoor levels. Consequently, studies typically determine outdoor and

indoor relationships of particulate matter. It has been difficult, however, to fully

separate the effects of indoor particulates from outdoor particulates.

B. Chemicals

1. Pesticides

Pesticides are a large class of compounds that includes organophosphates, carbamates, dicoumarins, and chlorinated hydrocarbons (Cooke 1991). Pesticides are

used in the indoor environment as insecticides, rodenticides, germicides, and termiticides in the control of insects, fungi, bacteria, and rodents. In a pilot study, the

EPA detected 22 diverse pesticides in the indoor air of homes, 17 of which were

detected in the breath of occupants. Monitoring data revealed that the five most

prevalent pesticides were chloropyrifos, diazinon, chlordane, propoxur, and heptachlor. Besides direct indoor application, indoor concentrations of pesticides may

originate from other sources such as pesticides applied outdoors that then become

airborne, or from pesticides that are carried indoors attached to foodstuffs or in the

water supply.

Short-term exposure to high concentrations of well-known pesticides, such as

heptachlor, aldrin, chlordane, and dieldrin, may result in headaches, dizziness, muscle twitching, weakness, tingling sensations, and nausea (EPA 1995b). Long-term

exposure may cause liver and central nervous system effects, as well as increased

cancer risk (EPA 1995b).

2. VOCs

Volatile organic compounds (VOCs) represent a large and diverse class of chemicals that possess the ability to volatilize into the atmosphere at normal room temperature (Samet et al. 1988; Cooke 1991). VOCs have been linked to the development

of sick building syndrome (Kostiainen 1995); however, the cause of this syndrome

is still unclear. Many of the VOCs that have been detected indoors are neurotoxic

(Cooke 1991). Clinical signs of VOCs consist of headache, nausea, irritation of the

eyes, mucous membranes, and the respiratory system, drowsiness, fatigue, general

malaise, and asthmatic symptoms (Becher et al. 1996; Kostiainen 1995).

Indoor exposure to these chemicals is considered widespread. The EPA has

identified 300 VOCs in homes (Cooke 1991). In a study of VOCs in the indoor air

of a number of households in Finland, clinical signs of VOCs disappeared after the

elimination of a localized emission source (Kostiainen 1995).

Formaldehyde is a well-known VOC of great public concern (Samet et al. 1988).

However, because of differences in measurement techniques, formaldehyde is not



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always included in studies of VOCs (Norback et al. 1995). This chemical was

classified under the EPA’s original weight-of-evidence rules as a probable (B1)

human carcinogen based on limited evidence in humans and sufficient evidence in

animals (EPA 1991b). The IRIS database also describes occupational studies showing significant associations between respiratory cancers and exposure to formaldehyde or formaldehyde-containing products, and nasal cancer in mice and rats exposed

by inhalation to formaldehyde.

Cooke (1991) describes noncancer effects of formaldehyde in humans including

irritation of the eyes and respiratory tract following acute-duration exposure. Cooke

also concludes that acute exposures to high concentrations (37–125 mg/m3) of

formaldehyde can cause respiratory distress, inflammation of the lungs, pulmonary

edema, and death.

3. Combustion Products

Combustion products represent a complex mixture of pollutants including carbon

monoxide, carbon dioxide, nitrogen oxides, particulates, sulfur dioxide, and wood

smoke. Carbon monoxide (CO) is a colorless, odorless gas that decreases the oxygencarrying capacity of the blood (Cooke 1991). CO can cause neurological effects

including headaches, dizziness, weakness, nausea, confusion, disorientation, and

fatigue (EPA 1995b). At high concentrations death may occur. Carbon dioxide is a

gas that can alter basic physiological functions at very high (> 30,000 ppm) concentrations (Cooke 1991).

Nitrogen oxides (NO, NO2, and N2O) are irritant gases (Cooke 1991). The acute

effects of NO2 on pulmonary function are well known (Cooke 1991). Acute effects

include increased airway resistance in asthmatics and healthy individuals, and

decreased pulmonary diffusing capacity. Chronic lung disease has been associated

with long-term exposure to nitrogen dioxide. Samet et al. (1987) describe animal

studies showing that NO2 exerts adverse effects on lung defense mechanisms (i.e.,

mucociliary clearance and alveolar macrophage) and indicate that the effects have

been demonstrated on the immune system.

4. Environmental Tobacco Smoke

Environmental tobacco smoke (ETS) is a complex mixture of gases and particles

that has received considerable public attention in recent years (OSHA 1994). Components of both mainstream and sidestream smoke are quite numerous; primary

components are respirable particulates, nicotine, polycyclic aromatic hydrocarbons,

CO, acrolein, nitrogen dioxide, and many other chemicals (Samet et al. 1987).

According to an OSHA assessment, the human health effects of ETS may include

irritation of the eye and upper respiratory tract, pulmonary effects (e.g., lung function

changes), cardiovascular effects (e.g., thrombus formation, vascular wall injury,

aggravation of existing heart conditions, chronic heart disease), reproductive effects

(e.g., low birth weight, miscarriage, increase in congenital abnormalities), and lung

cancer (OSHA 1994).



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C. Biological Contaminants

Biological contaminants represent a diverse array of biological agents that

includes viruses, molds, mildew, house dust mites, fungal spores, algae, amoebae,

arthropod fragments and droppings, and animal and human dander (Samet 1988;

EPA 1995). Exposure to biological contaminants can cause numerous health effects

such as allergic reactions (e.g., allergic rhinitis, asthma), infectious illnesses, hypersensitivity pneumonitis, humidifier fever, and Legionnaires’ disease.

Hypersensitivity pneumonitis and humidifier fever are immunologically mediated diseases with lung symptomology (Samet et al. 1988). The acute form of

hypersensitivity pneumonitis consists of fever, chills, cough, and dyspnea, while the

chronic condition involves progressive dyspnea and lung function impairment.

Fungi, bacteria, actinomycetes, amoebae, and nematodes have been identified as

culprits. Legionnaires’ disease is an acute bacterial infection resulting from indoor

exposures to Legionella pneumophila (Samet et al. 1988). Rhinitis, coughing, sneezing, watery eyes, and asthma are some of the characteristic symptoms (EPA 1995b).

Approaches to the study of airborne contagious diseases, including outbreaks

and epidemics, sampling during natural outbreaks, and experimental aerobiology

have been discussed by Burge (1995). Burge notes that evidence that a disease is

associated with indoor bioaerosols can be derived from: (1) case studies, or larger

epidemiological studies, (2) sampling the air to demonstrate that airborne transport

has occurred, or (3) experimental approaches (e.g., artificial transmission to animals

or humans).



IV. LIMITATIONS OF THE APPLICATION OF HAZARD

IDENTIFICATION TO INDOOR AIR POLLUTANTS

The identification of indoor air pollutants as potentially hazardous is complicated

because of limitations and uncertainties inherent in the risk assessment process. The

primary issues involve limitations of epidemiologic and animal studies, the nonspecificity of the symptomology of indoor air pollutants, and difficulties in the quantification of indoor air pollutant concentrations. These issues are discussed in more

detail below.

A. Limitations of Epidemiologic Studies

As mentioned earlier, epidemiologic data, whenever available, are particularly

useful in the hazard identification process. However, limitations that can affect

epidemiologic studies include a small sample size, characteristics of a study population that are not representative of the population as a whole, the lack of statistical

power, the presence of confounders, and uncertain exposure assessment. Studies that

utilize questionnaires can be subject to selection and information bias. Misclassification errors regarding exposures and uncertain symptom registration can occur.

Moreover, variables commonly examined in epidemiologic studies (e.g., subtle



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changes in lung function) are often prone to measurement error, and the relevancy

of such changes may be difficult to interpret from a clinical perspective.

The size of the population under study is of particular importance in the identification of hazards associated with indoor air pollutants (Weiss 1993). Because of

the relatively low levels of exposure to indoor air pollutants, and the limited variation

in exposure to indoor air pollutants in members of the population, a very large

number of subjects are required in a study to detect slight increases in the incidence

of an adverse health effect. Other important considerations of epidemiological studies of indoor air pollutants include an accurate and unbiased assessment of a particular health outcome, and the selection of an unbiased sample of exposed and

nonexposed individuals.

Confounding can be a serious problem in assessments of the associations between

exposure to indoor air pollutants and health hazards. Temperature, humidity, barometric pressure, concomitant exposure to outdoor air pollutants, and cigarette smoking are some of the examples of confounders that are not usually controlled in studies

of indoor air pollutants. The significance of confounders on the interpretation of

epidemiologic data has been shown in a recent study by Moolgavkar and Luebeck

(1996) on the association between particulate matter air pollution and mortality. For

example, they show that the small risks associated with exposure to particulate matter

could easily be attributed to residual confounding by copollutants. Moolgavkar and

Luebeck (1996) also emphasize the impact of methodologic issues (e.g., modification

of air pollution by seasonal effects), and the lack of appropriate statistical tools to

assess the contribution of the particulate matter component. They concluded that it

is not possible with the present evidence to show a convincing correlation between

particulate air pollution and mortality.

Numerous indoor risk factors, such as age, gender, ethnicity, socioeconomic

status, parental asthma, previous viral infection, hay fever, atopy, infant lung disease,

low birth weight, geographic region of residence, and household water damage, have

been identified as factors in asthma and wheezing. These symptoms are often linked

with indoor air pollutants (Maier et al. 1997). The failure to adjust for risk factors

can hinder interpretation of a study of indoor air pollution.

In recent years, there has been a growing awareness that psychological factors,

such as differences in the perception of odor and discomfort, and psychological

stress, may play an important role in the development of many of the nonspecific

and vague symptoms often attributed to exposure to indoor air pollutants (Rothman

and Weintraub 1995). There is evidence that stress, heavy work load, and conflicting

demands can influence the number and severity of reported complaints encountered

in the indoor environment (Nielsen et al. 1995). However, there are no well-designed,

carefully controlled studies that have specifically established the extent of the impacts

of such factors, or how to control for them in the design and performance of studies.

B. Nonspecificity of the Symptoms of Indoor Air Pollutants

One of the impediments encountered in the identification of the potential hazard

of an indoor air pollutant is the nonspecific nature of the purported symptoms. The



© 1999 by CRC Press LLC