TOXICITY AND RISKS INDUCED BY OCCUPATIONAL EXPOSURE TO CHEMICAL COMPOUNDS

5.3.1 Introduction and Background

5.3.1.1 Health Hazards Due to Occupational Exposure

Workers exposed to chemicals often experience discomfort and adverse

Health effects which may progress to occupational diseases. Even though

Working conditions have improved markedly during recent decades, in general

The number of individuals suffering occupational diseases has declined rather slowly. In addition, the number of new cases of registered occupational health diseases depends on employment circumstances; there is a natural decline dur­ing times of economic recession. This gradual change is due to several factors: the diagnostic criteria have become less stringent, physicians have learned to recognize occupational diseases better, and many occupational diseases de­velop slowly and thus the present situation reflects, at least to some extent, past exposures. Furthermore, the significance of occupational allergies has in­creased and allergic reactions can be caused even by low exposure levels.

Toxic chemicals, such as benzene and carbon disulfide, which in the past were common causes of occupational diseases, are nowadays generally well controlled. Most of the current occupational diseases are caused by exposures which are not particularly acutely toxic, but cause allergies. Typical exposures causing allergies are animal and flour dusts. If one considers actual chemicals, then isocyanates have become a major problem, principally via their ability to cause sensitization. Historical exposure to asbestos and other mining dusts still leads to numerous new diseases, many of which are very serious, even fa­tal. Solvents and pesticides are the groups of chemicals probably causing the largest amount of acute poisoning-type occupational diseases. l>2

Traditionally, the greatest risk due to chemicals has been considered to occur via inhalation. Chemicals may also penetrate through the skin. Water-based products are increasingly replacing solvent-based products in many applications, such as painting, printing, and gluing. The water-based products may, however, contain glycol derivatives which penetrate through the skin with ease. Many chemicals also irritate or sensitize the skin. Chromium, nickel, and epoxy resins are examples of common occupational skin allergens.

Ventilation engineers and occupational hygienists must be aware of the risks of chemicals with a high acute toxicity. Chemicals which are odorless (e. g., carbon monoxide), paralyze the sense of smell (e. g., hydrogen sulfide), or cause pulmonary edema as a delayed effect (e. g., nitrogen dioxide and ozone) are es­pecially insidious. Often these gases are produced as unwanted by-products. For example, nitrogen dioxide and ozone may be formed due to oxidation of air during welding. Welding near sources of chlorinated solvents, such as perchlo — roethylene, may cause pyrolysis and the formation of phosgene.

Occupational exposure limits (OELs) have been set in most industrial coun­tries to prevent excessive exposures. The limits for the most common exposures are based on experimental animal and epidemiological studies. Most novel agents have now generally gone through extensive toxicological testing. For the older chemicals, usually a plethora of epidemiological data is available.

When the incidence of occupational diseases was compared with the fre­quency of OEL violations in Finland, a rather good correlation was observed. This indicates that these OELs are reasonably well defined. This is also natural because they are based on long-term exposure history of a large number of people. However, the OELs for many chemicals are still only educated guesses, and numerous and often large changes have been made when the OEL lists have been revised. In addition, most chemicals still have no OEL. Only about 2000 chemicals have an OEL in some country.3

A particularly strict exposure-control policy is applied for carcinogenic chemicals. The OELs are usually lowered considerably even when a chemical

Is only suspected of being a carcinogen. When the evidence becomes stronger, the OELs are usually tightened further. Vinyl chloride provides a good exam­ple; its OEL was first lowered to 20 ppm from 500 ppm and then further to 3 ppm in Sweden in 1974-5 when its ability to cause a very rare type of cancer, angiosarcoma of the liver, was detected. The rarity of the disease made it pos­sible to locate the association; on the other hand, the practical impact of this carcinogenic potency also remains rather low. It has been estimated that less than 400 angiosarcoma cases will appear worldwide due to vinyl chloride ex­posure (in comparison with the number of occupational cancers caused by as­bestos which is already about 1000-fold higher).4-5 Internationally, there is an ongoing vigorous discussion on whether there are possible thresholds for genotoxic carcinogens. In many instances these compounds are considered to have no safe dose. If one assumes that there is some threshold also for geno­toxic carcinogens, this would have major consequences for the assessment of risks of carcinogenic compounds.6’8

Since the OELs provide the basis for ventilation requirements, an astute designer tries to find out how secure the OELs of the chemicals which will be used in the plant he or she is planning. Some of the chemicals used may totally lack OELs. Therefore, it is advisable to become familiar with the relevant liter­ature, preferably together with a specialist. It is clear that the ventilation engi­neer needs to be aware of the possible significance of toxicology for industrial ventilation construction.

The epidemiological data have the advantage of being based on human ex­posures. However, the results of epidemiological studies often remain inconclu­sive because of various confounding factors and poor exposure assessments. In addition, epidemiological data are available for only a small number of agents. The target level approach, presented in chapter 6 of this book, uses inherently large safety margins in relation to OELs. Unfortunately, it is also applicable only for the most common exposures. Since zero exposure is the best, the ALARA (As Low As Reasonably Achievable) principle, adopted in radiation protection, is, in principle, also a good approach for other exposures.9’10 However, even then the question, how low is low enough, may remain unanswered. This chap­ter has been written with the intention of lowering the threshold for a ventila­tion engineer to seek a toxicological consultation and to provide the fundamental background information needed to utilize the available toxicologi­cal literature. Occupational hygienists may also find the text to be a useful com­pact overview of the essential concepts of toxicology.

5.3.1.2 Epidemiology

Epidemiological studies usually consist of the knowledge obtained from human exposures supplementing data derived from experimental studies. Epi­demiological data often provide the ultimate proof of the deleterious effects of a chemical compound on humans, and form an important component of the assessment of the risks of some chemical compounds. In the future, the role of epidemiological data should be confirmatory rather than decisive in the risk assessment of existing and, especially, of new chemicals, since toxicology is be­coming more and more a preventive rather than an observational science in protecting the health of workers exposed to chemicals and mixtures of chemi ­cals in occupational environments.

The purpose of epidemiological studies is to try to identify whether there are causal relationships between the occurrence of diseases or other biological effects and exposures to various agents. There are three main types of epide­miological studies: cross-sectional, cohort, and case-control studies. The working population is, on the average, healthier than the general population. Due to this “healthy worker effect,” comparisons should be made with an­other worker group instead of the general population. The reason for the healthy worker effect is the fact that it is difficult for sick or disabled people to stay in employment due to the limitation caused by their diseases. Poor health may also prevent a person from getting a job in the first place.

Cross-sectional Studies

In a cross-sectional study, exposure and effect are studied simultaneously. This approach contains an inherent problem because exposure must precede the effect. However, it can be used to investigate acute effects and also mild chronic effects (which do not force people to leave their jobs) if exposure has remained rather stable for a long time. When the prevalence of the effects studied are compared with the prevalence in other worker groups (controls or references) which correspond otherwise with the study group but are not ex­posed to the agent investigated, indicative evidence of possible causality may be obtained. For example, cross-sectional studies have been applied success­fully to reveal the associations between mild neurotoxic effects and exposure to organic solvents.11

Cohort Studies

In a cohort or follow-up study, a group of workers exposed to the same agent is followed for a certain period, which can be either retrospective (starts at some time in the past and continues to the present) or prospective (starts in the present and continues for a certain time into the future). A cohort of controls should be formed with the same selection criteria as used for the study groups, except that they lack the exposure. Thus, exposure to one agent only can be studied whereas several health outcomes can be included. A cohort study is the only possible study method when the exposure studied is rare. The results of the cohort study are expressed as relative risks (risk ratios, RR) for various diseases (see Table 5.8 for results of different types of epidemiological studies on cancers in printing workers and epidemiological terms) (IARC, 1996),

Relative Risk (RR) = (exPosefd-^……………. diseasej/^U exposed)

(controls with disease)/(all controls)

A,, r> ■ mm (exposed cases)/(non-exposed cases)

Odds Ratio OR) = ———

(exposed controls)/(non-exposed controls)

The benefit of a prospective cohort study is the possibility for accurate ex­posure assessment. However, these are not common, because many occupa­tional diseases (including cancers which are being intensely investigated currently) require long exposure times to develop. It is not practical or ethical to wait for decades before one obtains the result.

The problems often encountered in retrospective cohort studies include poor exposure data and incomplete follow-up of all individuals. The accuracy of health outcome data may also be low.

Reference,	Period of		Cancer site/	No.
Country	Study subjects follow-up	Occupation/exposure	Cause of death	Obs.	RR	95% Cl	Comment
Malket and	24 652 men and 1961-73	Printing workers (M)	Lung	190	1.5	[1.3-1.8]	Morbidity
Gemne,1 ’	6450 women	Blue-collar workers (M) in	Lung	149	1.6	[1,4-1.9]
Sweden	Registered at 1960 census as printing workers	Printing enterprises (newspaper, journal/book printing, others)
		Birth cohort around 1990 (M)	Lung	45	1.9	1.4-2.5
			Urinary bladder	76	1.3	NG	P > 0.01
			Kidney	48	1.1	NG	P > 0.01
			Skin melanoma	27	1.2	NG	P > 0.01
		Printing workers (F)	Lung	9	1.3	NG	P > 0.01
			Urinary bladder	5	0.8	NG	P > 0.01
			Kidney	7	1.1	NG	P > 0.01
			Skin melanoma	8	1.2	NG	P > 0.01
			Cervix/uterus	162	1.3	[1.1-1.5]
McLaughlin	Male printing 1961-79	Printing industry	Skin melanoma	91	1.4	[1.1-1.7]	Morbidity
Etal. (1988)	Workers at 1960	Newspaper printing industry		39	1.9	[I, 1-1.7]
Sweden	Census;	Newspaper publishing industry		7	3.1	|1.2-6.4|
	91 melanomas	Typographets in newspaper printing industry Machine repairers in newspaper printing industry Journalists/editors in newspaper printing industry Business/executives in newspaper printing industry		19 2 16	2.0 14.5 2.4 9,1	[1.2-3.1] [1.6-52.3] [1.4-3.9] [2.9-21.2]

(continues,/

Reference, country	Study subjects	Period of follow-up	Occupation/exposure	Cancer site/ cause of death	No. Obs	RR	95% Cl
Aronson and	242 196 women	1965-79	Printing and publishing	Breast	11	2.2	1.1-3.9
Howe	Identified through		Industry
(1994)	Employment survey
Canada
Costa et al.	1981 population	1981-89	Printing and publishing	Pleura	2	6.0	0.7-22
(1995)	Census of Turin,		Industry (M)
Italy	Italy, residents;			Colon	7	2.1	0.9-4.4
	10 798 deaths
				Lung	22	1.1	[0.7-1.71
	Among persons
	Employed			Urinary bladder	2	1.0	[0.1-3.6]
				Haematopoietic	7	1.6	0.6-3.3
			Printing and publishing	Lung	3	2.6	0.5-7.6
			Industry (F)	Colon	2	2.7	0.3-9.7
				Ovarian	3	3.2	0.6-9.3
				Haematopoietic	2	2.0	0.2-7.2
			Printers (M)	Liver	3	1.7	0.3-5.0
				Colon	3	1.8	0.4-5.3
				Multiple myeloma	2	[9.7]	[1.1-33.1]
				Lung	12	1.2	[0.6-2.1]
				Urinary bladder	0	—	—
Costa et al.	.1981 population	1981-82	Printing and publishing	Kidney	3	4.8	1,7-13.4
(1995)	Census of Italian		Industry (M)
Italy	Residents;
	15 734 deaths
	Among persons
	Employed
				Lung	11	1.1	[0.8-1.4]
				Urinary bladder	N Z.	2.9	[0.8-11.1]

Comments

Mortality; other sites not significantly elevated Mortality

244

Mortality

L’ukka la «1995} Finland

Morbidity

1970 population 19/1-83 Printing occupa- census tions (M)

47 178 men,

46 853 women

Printing occupa­tions (F)

Printers (F)

Printers (M)

Lithographers

Colon	16	2.2	1.2-35.
Lung	50	0.8	0.6-1.1
Colon	10	1.4	0.7-2.5
Lung	12	1.8	0.9-3.2
Breast	74	1.4	1.1-1.8
Ovarian	30	2.2	1.5-3.1
Skin melanoma	5	1.1	0.3-2.5
Skin melanoma	7	1.1	0.5-2.4
Urinary bladder	9	1.1	0.5-2.0
Leukemia	2	0.4	0.1-1.4
Lung	19	1.1	0.7-1.7
Skin basal-cell	4	4.4	1.2-11.2

Carcinoma

RR, relative risk estimated by SMR (for mortality) or SIR (for morbidity); M, male; F, female; NG not given.

International Agency for Research on Cancer (1996) “Printing processes and printing inks, carbon black and some nitro compounds”. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 65, pp. 67-70. International Agency for REsearch on Cancer, Lyon, France.

No. of exposed Reference, Country Type of controls Exposure Sex Cases/ Controls Odds Ratio 95% Cl Comments Najem et al.18USA Hospital-based, tobacco — related heart diseases and neoplasms excluded Printing industry (> 1 year) M + F 7/5 -} ’7 0.8-9.6 Crude odds ratio Cartwright19 United Kingdom Hospital-based, non — malignant diseases Printers (exposed to Ink-fly from high-speed presses) M + F 18/NG 3.1 1.4—6.8 Adjusted for type of case (incident or prevalent) and sex Silverman et al.20 USA Population-based Printing industry (ever) Printers (ever) M M 50/45 6/2 1.1 3.0 0.7-1.7 0.6-14.8 Crude odds ratio Schoenberg et al.21 USA Population-based Printing workers (ever) Printing ink (self-reporting) M M 20/38 42/53 0.9 1.6 0.5-1.5 1.0-2.5 Adjusted for age, smoking, and other employments Baxter and McDowall22 United Kingdom Other cancers All causes of death Printers (stated on death certifi­cates) M 21/NG 1.5 1.2 P 0.05 P 0.05 Against other cancers; matched on residence, year of death, age Brownson ec al.2-1 Population-based, other Printing machine M 7/S 3.1 1.1-8.9 All controls Prostate cancer Non-smoking-related Operators (longest-held job) M 7/6 2.3 0.8-7.2 Excluded Silverman et al.2S — ^ USA Population-based Printer (ever) M (white) F 37/77 1/10 0.8 0.2 0.5-1.2 <0.1-1.4 Adjusted for smoking; fre­quency matching for age and geographic area Kunze et al. 27 Hospital-based, non-neo­ Printing industry (ever) M 11/3 5.0 1.3-19.6 Crude odds ratio Ftance Plastic diseases of the lower urinary tract Printing worker (ever) M 7/3 3.0 0.7-13.8 Cordier et al.2K France Siemiatycki et al.29, Hospital-based, neoplas­tic. respiratory and urological conditions excluded Population and hospital- Printing and publishing industry (ever) Printers Printing and publishing industry M M M 26/28 14/9 0.9 1.5 0.5-1.5 0*6-3.5 Adjusted for age, hospital residence, smoking Adjusted tor age, family Canada Based, other cancers, excluding lung and kidney sites < 10 years > 10 years Photo­graphic products (substantial exposure/ 2/NG Il/NG 4/NG 0,3 1.9 3.0 0.1-1.2 0.9-3.9 0,9-10-1 Miomi, si toking, coffer i-onsumpriotT, ethnicity, respondent status

Reference,				No. of exposed	Odds
Country	Type of controls	Exposure	Sex	Cases/controls	Ratio	95% Cl	Comments
Coggon et al.-®	Deaths from other	Printing inks	M	28/36	1.6	0.9-2.7	Job exposure matrix
(1984)	Causes	Printing inks (high exposure)	M	9/9	2.0	0,8-5.0	Applied to occupa­
United Kingdom							Tions recorded on death certificates; age <40 years, cases and controls
Schoenberg et al.31	Population-based	Printing workers >10 years	M	20/11	2.5	1.0-6.1	Adjusted for smoking
USA			M	7/1	8.4	NG	(p.20,05, crude)
		Printing industry	M	37/31	1.3	0.8-2.3	Adjusted for smoking
Benhamou et al.~i2	Hospital-based, non­	Printers and related	M	32/51	1.2	0.7-1.9	Matched for sex, age at
France	Tobacco related diseases	Workers					Diagnosis, hospital, interviewer; adjusted for smoking
Hoar Zahm et al.53	Selected cancer sites	Printing occupations	M	21/41	1.1	0.6-1.9	Adjusted for age, smoking
USA				7/[4] (adenocarci­ Noma)	1.8	0.7-4.2	Occupations unknown for about half of cases and controls
Siemiatycki54	Hospital-based,	Printing and publishing	M	35/NG	2.0	[1.2-3.5]	Smoking-adjusted
(1991)	Other cancers	Industry
(Canada)		Printers	M	26/NG	2.1	[1.1-4.1]	Smoking-adjusted
		Printers (>10 years)	M	13/NG	1.7	[0.7—4.1 ]	Smoking-adjusted
		Printing process workers	M	15/NG	3.1	[1.1-8.7]	Smoking- ad j usted
			M	6/NG (adenocarci­	7.0	[1.8-27.9]	S m oking — a dj usted
		Inks (any)	M	Noma )	1.6	[1,0-2.7]	Smoking-adjusted
		Inks (substantial)	M	37/NG 18/NG	1,5	(0.7-3.11	Smoking-adjusted

Case-control Studies

In case-control studies, only one disease can be investigated. The cases in­clude all patients with a certain disease observed in a hospital, city, or a larger area in a given period of time. Their exposure histories are compared with those of the controls. Thus, several exposures can be investigated. The expo­sure data are not very accurate because they are obtained by interview. Espe­cially in cases of serious diseases, patients are often desperate to seek some reason for their disease. Therefore, patients of some other disease are usually employed as controls to avoid this information bias. The selection of controls is a crucial but extremely difficult task. Since factors such as age, sex, smok­ing, living habits, and place of abode are known to be risk factors for several diseases, the effects of these confounding factors are eliminated b matching. However, overmatching should also be avoided. Odds ratio (see Table 5.8b, c) is used to express how often the cases have been exposed to various exposures compared to controls. Case-control studies are common because they are in­expensive and relatively easy to perform. If the disease studied is rare, this ap­proach is also the only practical alternative.12

5.3.1.3 Classifications of Toxicology

The word toxicology originates from the Greek word toxicon, which means arrow. In ancient times, arrows were dipped into plant poisons to in­crease their lethality in hunting. Today, toxicology refers to that scientific dis­cipline that explores the deleterious effects of chemicals or of physical or biological factors on living organisms. Toxicology also explores the mecha­nisms whereby chemicals, or physical or biological factors induce their harm­ful effects in the organism.

There are several definitions and classifications of toxicology. One classi­fication is based on the target organs which are harmfully affected by chemi­cals. Hence, there are terms such as neurotoxicology, liver or hepatic toxicology, kidney or renal toxicology, and toxicology of the eye (ocular toxi­cology). Inhalational toxicology emphasizes the importance of the lungs as the target organ of chemicals. In addition to these descriptive classifications, toxi­cology can be divided into mechanistic toxicology, conducted mainly in uni­versity and governmental research institutions, and descriptive or regulatory toxicology, which is required for classification and labelling of chemicals for registration purposes. Even if mechanistic toxicology is essential for under­standing how chemicals and other factors induce their toxic effects, descrip­tive toxicology is also important in characterizing the properties of a chemical compound. Descriptive toxicology is a prerequisite for regulatory purposes and risk assessment. When the qualitative requirements for risk assessment in­crease, the importance of mechanistic information on chemicals in risk assess­ment wilt also increase.

Toxicology can also be divided into different classes based on the goals it serves. Clinical toxicology explores ways of treating poisoned patients, and also aims to develop quick methods to diagnose poisonings. Forensic toxicol­ogy is the science involved in detecting the role of poisons in fatalities. Environ­mental toxicology assesses the importance of environmental pollution and the effects of exposure through various environmental compartments on human health. Ecotoxicology is interested in the effects of environmental chemicals on

.3 TOXICITY AND RISKS INDUCED BY OCCUPATIONAL EXPOSURE TO CHEMICAL COMPOUNDS HHH1 TABLE 5.9 Classifications of Toxicology Area of toxicology Scope Meehan оatic Understanding of cellular and molecular mechanisms Regulatory Drafting regulations and legislation Organ-specific Defining organ-specific effects and defining chemically mduccd critical effects Forcnsic Diagnosis and fatalities Occupational Delineating occupational hazards and risks and prevention Environmental Identification of chemical hazards in the environment, and their effects on humans and wildlife species Clinical Diagnosis and treatment of poisoning

Animals such as fish, insects, birds, and other wild animals. Industrial or occu­pational toxicology aims to study the effects of chemicals on workers exposed in an occupational environment (see Table 5.9).

Toxicology often provides the basis for a number of regulations aimed at protecting workers from potentially harmful effects. Today, more than ever before, toxicology has a preventive function that provides information on chemicals that can be used safely. It is difficult to imagine occupational or other safety regulations without a major input from toxicology.

The main role of toxicology in the industrial setting originates from its ability to identify harmful chemicals and other hazards in advance. After toxi — cological research has identified exposure-effects relationships for different chemicals, occupational exposure limits (OELs) for various industrial chemi­cals can be established. Subsequently, workers can be protected against exces­sive exposures by measuring the exposure and ensuring that the OELs are not violated; ventilation engineers and occupational hygienists are the key persons in this field. Careful planning and design can ensure that most workers can be protected, nevertheless the most sensitive individuals may still react to expo­sure levels that are below the acceptable exposure limits. These relationships also indicate the close relationship between industrial toxicology and indus­trial hygiene. Without a broad knowledge of the toxicological characteristics of chemicals, industrial hygiene is more or less irrelevant. On the other hand, without industrial hygiene, toxicology would be helpless in protecting the workers against chemical hazards.

5.3.1.4 Industrial Toxicology, Hygiene, and Occupational Medicine

Industrial toxicology, industrial hygiene, and occupational medicine all have a common goal: to protect workers from occupational hazards in the workplace. The goal of toxicological research is to protect the worker by characterizing the biological effects of chemicals and by identifying the haz­ardous agents, whereas the goal of occupational hygiene is to protect work­ers by improving the occupational environment. The goal of occupational medicine, in turn, is to protect workers’ health by identifying early signs of harmful effects, and to diagnose and treat occupation-related diseases. In

Many cases, reduction of exposure will suffice to prevent many occupation — related diseases after the first symptoms, but the exposure may also need ro be stopped completely. However, before such radical measures can be taken, the association between the exposure and the disease has to be estab­lished, i. e., the occupational nature of the disease needs to be demonstrated. Therefore, occupational medicine relies on toxicological and occupational hygienic knowledge in solving occupational health problems. However, the scope of occupational medicine is much wTider than simply examining chemical-induced toxicity, as it covers a wide area of interests such as occu­pational ergonomics and psychophysiological factors in the occupational setting.35

Poisoning Incidents in the Workplace

The hazards of chemicals are commonly detected in the workplace first, because exposure levels there are higher than in the general environ­ment. In addition, the exposed population is well known, which allows early detection of the association between deleterious health effects and the exposure. The toxic effects of some chemicals, such as mercurv com­pounds and soot, have been known already for centuries. Alreadv at the end of the eighteenth century, small boys who were employed to climb up the inside of chimneys to clean them suffered from a cancer of the scrotum due to exposure to soot. This was the first occupational cancer ever identi­fied. In the viscose industry, exposure to carbon disulfide was already known to cause psychoses among exposed workers during the nineteenth century. As late as the 1970s, vinyl chloride was found to induce angiosar­coma of the liver, a tumor that was practically unknown in other in­stances.36

Even in the Nordic countries, exposure to carbon disulfide still caused severe central nervous effects among exposed workers during the late 1960s and early 1970s, and exposure to lead caused several lead poisonings at the same time. Exposure to asbestos remained a major health hazard until the 1970s. The use of asbestos is nowadays strictly controlled and it has been banned in many countries. Nevertheless, it continues to be an important oc­cupational health problem because of the long latency period of asbestos for causing lung cancer and mesothelioma, a time period of 20^10 years. In ad­dition, there are large amounts of asbestos remaining in buildings, and reno­vation of old buildings will pose a health risk to workers for a long time to come.37

Many very hazardous solvents, such as benzene and carbon tetrachloride, were widely used until the 1970s. The situation was very similar for the use of pesticides. Among the toxic pesticides that were still in wide use 20 years ago were chlorophenols, DDT, lindane, and arsenic salts, all of which are classified as human carcinogens as well as being acutely toxic.4’3K Fortunately, use of these kinds of very toxic chemicals is now limited in the industrialized world. However, because the number of chemicals used in various industries contin­ues to increase, the risks of long-term health hazards due to long-term expo­sure to low concentrations of chemicals continues to be a problem in the workplace.

Association of Industrial Activity and Poisonings in the General Environment

The harmful effects of industrial emissions are not confined to the work­ers but extend beyond the plant boundary line. Chemically-induced diseases among workers exposed to industrial chemicals are a warning sign of the risks to which a larger population is also being exposed; usually the chemical haz­ards are in principle similar in the occupational and general environment. However, occasionally environmental exposures can be qualitatively different from the occupational environment and may also cause deleterious health ef­fects in the general population.59’40

Since the general population is much larger than the occupationally ex­posed worker groups, and also includes very sensitive individuals, some del­eterious effects have been detected only in the general population. Urban air pollution is a good example. In the 1930s, an air pollution incident in the valley of the River Maas in Belgium was responsible for the deaths of tens of individuals due to increased concentrations of coal dust and sulfur dioxide in the ambient air. At that time, it was already predicted that this could be a harbinger of future catastrophes in a major city like London, and, indeed, in 1952, a dramatic increase of concentrations in small coal particles and sul­fur dioxide took place during weather inversion in the London metropolitan area. In consequence, an excess mortality of more than 4000 individuals oc­curred during a few days. Similar though less severe smogs (a fog caused by air pollution) took place in the late 1950s. Subsequently the use of coal was prohibited in London and today the air quality in the city is much better than it was 40 years ago. In addition to this classic kind of smog, photo­chemical smog, consisting of nitrous oxides and ozone and their reaction products with hydrocarbons, is encountered in warm and sunny areas where there is major traffic-related pollution. A model area for such a situation is Los Angeles, California, where the air quality is a continuous concern.41

The emphasis on air pollution in different parts of the world has led to marked improvements in air quality. However, there are several metropolitan areas in the world where the air pollution situation is still deteriorating. Ex­amples of such areas are Mexico City, Mexico, New Delhi, India, Cairo, Egypt, and Sao Paulo, Brazil. Most of these badly polluted areas are in devel­oping countries where resources for improving the situation are limited. Thus, these problems are difficult to solve (see Fig. 5.30).41

Recently, much emphasis has been put on the harmful effects of small par­ticles, i. e., particulate matter (PM), on human health. A number of standards have been established to characterize the PM fractions in the air and their ef­fects on human health. A widely used PM standard in force in both Europe and the United States is based on the mass concentration of particles with a di­ameter of 10 |xm or less (PM10). However, recently the U. S. Environmental Protection Agency (EPA) proposed a new standard that is based on the aero­dynamic diameter of 2.5 jjim particles. This new standard emphasizes the sig­nificant impact of small particles on human health, especially on the respiratory and cardiovascular systems.41,42

It has been known for years that professional bus and truck drivers as well as railroad workers suffer a larger than average risk of lung cancer because of

Mega-cities

0 200 400 600 800 1000 1200 ■■ FIGURE 5.30 Comparison of ambient levels of I h maximum ozone, annual average of total sus­pended particulate matter (TSP), and sulfur dioxide in selected cities from around the world to illus­trate the variation in these levels from country to country with respect to the United States. (Reproduced from the National Air Quality and Emission Trends Report ( 1992), with permission.]»1

Bangkok Beijing Bombay Buenos Aires Cairo Calcutta Delhi Jakarta Karachi London Los Angeles Manila Mexico City Moscow New York Rio de Janeiro Sao Paolo Seoul Shanghai Tokyo

Exposure to gas engine, especially diesel engine, exhausts. These individuals are also at a larger than average risk of sudden death due to myocardial in­farction, cardiovascular disease, and pulmonary disease. Several studies from the U. S. and Europe have demonstrated that exposure to inhalable particles, especially those generated by traffic and energy production, cause a one to five percent increased risk of mortality among the general population. At the Eu­ropean level, this would represent 50 000 to 100 000 additional deaths annu­ally.43,44 It is probable that the previous examples of increased mortality during historical air pollution episodes were largely due to exposure to small particles. Unfortunately, no clear conclusions can yet be made concerning oc­cupational dust exposure in general.

5.3.1.5 Concept of Risks

The term risk has wide implications. It is used to characterize difficulties in predicting changes in the currency markets and to indicate the probability of potential financial losses due to such changes. A surgeon prior to a major operation also needs to evaluate the risks to the patient, not only due to the disease, but also risks associated with the operation itself and the anesthesia. Car drivers seldom consider the risk of a traffic accident when starting a car even though the risk of a fatal car accident is many rimes greater than the cal­culated risks associated with exposure to chemicals. Another example, widely discussed in the media, is the comparison of risks from energy production by fossil fuels and nuclear energy. This comparison has proven to be extremely difficult due to a number of philosophical aspects. We can calculate with some degree of certainty the risks involved in the production of energy with

Fossil fuels. There are major risks in mining or oil drilling, during the trans­portation of the fuel, and due to the extensive emissions emanating from the combustion of the fuel. In Europe, annual loss of life due to energy produc­tion utilizing fossil fuels, and due to traffic exhaust, is close to 100 000. The verifiable health hazards due to nuclear energy are only a small fraction of the losses due to the use of fossil fuels. However, the potential risk due to a nuclear accident raises alarm in individuals, because the true risk due to nu­clear energy cannot be calculated. Even if the accident probability is small, the losses due to even one incident may be catastrophic. This is well illus­trated by the accident in Chernobyl in 1986.4j’46

If one is to estimate the potential hazards of some chemicals prior to their release to the market, the chemicals must be tested for their toxicity in experi­mental animals. Animals are exposed to high doses of chemicals to avoid the use of large numbers of animals. When the results of animal experiments are applied to humans, several assumptions have to be made, including (1) that animals are a good model to predict human hazards caused by chemicals, and (2) that large doses of chemicals used in studies utilizing small groups of ex­perimental animals cause similar effects to what would be seen in humans though at a lower frequency or with a milder change in functions of target or­gans. Toxic effects of chemicals may, however, be quite different in rodents than in humans. For example, guinea pigs tolerate the effects of strychnine rather well, in contrast to humans. For organ toxicity (neurotoxicity, liver tox­icity, kidney toxicity) endpoints, safety factors can be used for assessing safe levels for humans {see below). Dose-responses are regularly used to delineate the toxicological characteristics of chemical compounds, and to make com­parisons of effects between species.1’47

In most cases, experimental animal studies are used to define the so-called no-observable-adverse-effect level (NOAEL), i. e., the lowest dose that does not cause an adverse effect in experimental animals. This dose is then divided by a safety factor of 100, ten for interspecies differences between rodents and humans and ten for intraspecies differences between humans, to calculate the dose (mg/kg) which is considered to be safe for humans. This approach con­tains the assumption that there is a safe dose below which a chemical does not cause harmful effects on humans (for the safety factor of 100, see Fig. 5.31). This assumption of a safe threshold dose is used for most endpoints of deter­ministic toxicology, i. e., organ toxicology. However, whether in fact there can be any safe dose for carcinogens, especially for genotoxic carcinogens, has been challenged, and the linear extrapolation models widely used in carcino­genic risk assessment do not utilize safety factors. However, this approach has also been recently challenged because throughout biology, one does not find effects without any threshold, and because it neglects biological defence mech­anisms present within cells. The thresholds may, however, be so low in some instances that the arguments are purely theoretical. However, they have im­portant implications for risk assessment.47’49 Furthermore, one can argue that none of the toxicological endpoints, whether deterministic (organ toxicity) or stochastic (cancer) in nature, have a threshold. This may be true conceptually, and it is especially true experimentally because in most cases determination of a true threshold is beyond the limit of detection of the experimental approach.

Interspecies		Interindividual
Differences		Differences
10-fold		10-fold

100-fold uncertainty factor

Toxico — dynamics 100.4

Toxico­ Kinetics 100.6 (4.0)

T oxico — dynamics ‘ lO0-5 (3.2)

Toxico­ Kinetics LO«-‘ (3.2!

(2.5)

FIGURE 5.31 Subdivision of the 100-fold uncertainty factor showing the relationship between the use of uncertainty factors (above the dashed line) and proposed subdivisions based on toxicokinetics and toxicodynamics. Actual data should be used to replace the default values if available.48

Usually risk assessment procedure, discussed in more detail later (see Chapter 6), is divided into four different stages or steps (see Fig. 5.32):49

1. Hazard identification through animal experiments, epidemiological studies, or structure activity analyses

2. Hazard characterization, or dose-response characterization, by using experimental animals to reveal target organs and toxic doses, and the shape of the dose-response curve

3. Exposure assessment to reveal the exposure of different groups of people, and to compare their exposure levels to the doses that cause harmful effects in humans as shown in epidemiological studies, or to doses that cause toxic effects in experimental animals

4. Risk assessment, a synthesis of the preceding three steps, which aims to assess both qualitatively and quantitatively the risks induced by a chemical at a given or at different exposure levels.

This step utilizes either a safety factor approach or various extrapolation models.

Based on the results of risk assessment, decision makers have to at­tempt to manage risks, e. g., by determining various exposure limits to protect individuals against deleterious effects of chemical exposures. This kind of procedure is commonly used for determining acceptable daily in­take values (ADIs)49 for contaminants in foods and acceptable operator exposure level (AOELs) for pesticides. Even though the results obtained in experimental animal tests are part of the basic data on which the OELs have been based, the levels result from consideration of many other as­pects, especially epidemiological data. In addition, these decisions take into consideration economic and political consequences of the decisions, as well as perception of various risks by the general public. Furthermore, properties such as strong odor or irritation influence the levels of OELs. It needs to be kept in mind that even though risk assessment of exposures

Research, Risk assessment Risk managernnet

Toxicity assessment: hazard identification and dose-response assessment

A

Laboratory and field observations		Development of regulatory options
Information on Extrapolation Methods
Evaluation of public health, economic, social, political consequences of regulatory options
Risk Characterization
Research needs identified from risk assessment process

Agency I Decisions | And actions
Field Measurements, characterization of populations	Exposure Assessment Emissions Characterization

FIGURE 5.32 Elements of risk assessment and risk management.49(used with permission.)

To single chemicals is still far from complete, much greater difficulties are encountered in assessing the risks of multiple exposures.

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