Chemical Hypersensitivity and the Allergic Response

[Guest guest]

*

 

Chemical Hypersensitivity and the Allergic Response

by William J. Rea, M.D.

_http://www.satori-5.co.uk/word_articles/mcs/chemical_hypersensitivity.html_

(http://www.satori-5.co.uk/word_articles/mcs/chemical_hypersensitivity.html)

Reprinted from the Ear, Nose, and Throat Journal, Vol 67, No 1, January

1988. Published by Little, Brown and Company, Boston, MA. All rights reserved.

No

part of this reprint may be reproduced in any form or by any electronic or

mechanical means, including information storage and retrieval systems, without

the publisher’s consent.

About the author . . . . William J. Rea, MD, FACS, FACA, is director of the

Environmental Health Center—Dallas, and he is a practicing cardiovascular

surgeon in Dallas, TX.

The widespread chemical contamination of the earth’s air, food, and water

with its effects on various biological systems has been described in nearly

5,000 scientific articles. At present, chemical sensitivity can be defined as

an

adverse reaction to ambient levels of toxic chemicals, which are generally

accepted as being " subtoxic, " in environmental air (home and public

buildings), food, and water.1 The manifestation of adverse reactions depends on

the

tissues or organs involved, the chemical and pharmacologic nature of the

substances involved, the individual susceptibility of the exposed person

(nutritional state, genetic make-up, and toxic load at the time of exposure),

the length

of time, amount, and variety of other body stressors (total load), and the

possible synergism among these at the time of reaction.

It is often difficult, and at times impossible, to distinguish between

allergic and toxic responses, and chemical sensitivities may encompass both.

Chemical allergies involve an IgE or IgG response, and are a small but

significant

part of the overall spectrum of chemical sensitivity. An example is the

IgE-mediated toluene diisocyanate antigen-antibody reaction. Another type has

been found in survivors of acute poisoning who develop chemical sensitivity,

but

is usually not IgE- or IgG-mediated. In two large incidences—the gassing of

troops during World War I and the cyanide accident in Bhopal, India—exposed

persons have developed chemical sensitivities. In contrast, the etiology of

those who have become chemically sensitive following long-term subacute toxic

exposures is often difficult to discern. A significant number of persons are

involved, perhaps as much as 20% of the population. The chemically sensitive

person may develop reactions quite suddenly or gradually over a period of

years. The concentration of chemicals needed to trigger a response diminishes

and

reaction to a minimal amount of toxic chemical may be possible. This

progression is probably related to an overload of the enzyme detoxification

systems.

Chemical sensitivity is usually manifested in one main organ with secondary

effects in others, and symptoms are usually multiple. The end-organ responses

are often in the smooth muscles of neuro-cardiovascular, gastrointestinal,

urogenital, and respiratory systems, as well as the skin, but any organ may be

involved.

Much of the controversy about chemical sensitivity stems from the clinician’

s inability to recognize the occurrence of environmental overload with

subsequent application of appropriate clinical diagnosis and treatment to the

individual patient.

Pathophysiology

The total body load is the total of all incitants to which the body has to

respond to maintain homeostasis.1 Pollutants may be biological (pollens,

dusts, molds, viruses, bacterias), chemical (organic or inorganic), or physical

(heat, cold, electromagnetic radiation, light, radon, and positive and negative

ions). To prevent disease, the body must manage this burden through use or

elimination. If the load is excessive, symptoms may occur as a response to

disturbance of the body’s immune and enzyme detoxification systems.1

Acute toxilogic tolerance (masking, adaptation) is a change in the

homeostasis (steady rate) induced by the internal or external environment, with

accommodation of body function adjusting to a new set point.2 This adaptation

or

masking is an acute survival mechanisms in which the person apparently adjusts

to a constant acute toxic exposure to survive initially but then later pays

the price with a long-term decrease in efficient functioning and, perhaps,

longevity. Because of this phenomenon, the total body load may increase without

the person knowing. Even though no correlated symptoms are apparent, repeated

exposures continue to damage the immune and enzyme detoxification systems,

and the eventual result is end-organ failure. Avoidance of the offending

substance for four days may unmask associated symptoms. Initial withdrawal

symptoms may even occur. However, subsequent re-exposure will produce an

immediate

and clearly definable reaction because cause and effect are easily

distinguished.

When exposed to a toxic substance, the body initially develops a bipolar

response, with a stimulatory phase followed by a depressive phase.3 Induction

of

the detoxification systems occurs. If the incitant is virulent,

biochemically active, or of substantial volume or duration, the detoxification

systems

may be depleted (depressed) by overstimulation. At the same time, a person may

perceive a stimulatory reaction in the brain and initially feel that the

inciting substance is not harmful but actually pleasurable. Therefore, the

person

may continue to subject him or herself to more exposures; with time (minutes

to years), however, the body’s defenses can break down and

depression-exhaustion symptoms develop. This stimulation and the resultant

response has been

observed with many pollutant exposures, including ozone.

Biochemical individuality accounts for individual susceptibility. Each

person has differing quantities of carbohydrates, fats, proteins, enzymes,

vitamins, minerals, and immune parameters with which to respond to

environmental

factors. This individuality allows us to clear noxious substances or to

contribute to our own body burden. Biochemical individuality depends on at

least

three factors: genetics, the state of the fetus’s nutritional health and

toxic

body burden during pregnancy, and the person’s toxic body burden in later

life

in relation to nutritional state at the time of exposure. For example, some

persons are born with significantly less of a specific enzyme. Although that

person may be able to respond to an environmental stimulant, this response is

often considerably less than that of the person who was born with 100% of the

expected detoxifying enzyme and immune parameters.

Environmental Pollution

Recent studies have shown that nearly half of the world’s pollutants are

generated by man,4 accentuating the problem described by Randolph5 more that 30

years ago. Literally thousands of synthetic chemical products heretofore

believed innocuous have been incriminated as agents of homeostatic dysfunction.

With the findings that sensitivities occur in association with picomolar

quantities of chemical agents has come the discovery that procedures such as

skin

prick or scratch tests often fail to demonstrate positive reactions that are

clinically verifiable by other means.

Recent literature verifies previous findings regarding the harmful effects

of certain chemical incitants, such as formaldehyde, phenol, chlorine, and

petroleum alcohol.6 Commonly encountered chemicals, such as glycine,

chlorphenothane, toluene, and turpentine, have been associated with the

triggering of a

plethora of vascular alterations,7-9 and some familiar metals, among them

nickel, cobalt, chromium, aluminum, and mercury, have been implicated.10 Other

common environmental chemical incitants include xylene, benzoyl peroxide,

carbon tetrachloride, sulfates, and isocyanates.

Water Pollution

Minerals, toxic organic and inorganic chemicals, particulate matter, and

radiation play an important role as pathways for chemical contaminants entering

the human organism. The incidence of many chronic diseases (coronary disease,

hypertension, and stroke) is associated with various water characteristics,

including purity, hardness, and softness.11-13 Protective agents found in

hard water are calcium, magnesium, vanadium, lithium, chromium, and manganese.

Certainly, once cardiovascular pathology is induced, waters with high sodium

content may be counterproductive. Suspected harmful agents include cadmium,

lead, copper, and zinc, which tend to be found in higher concentrations in

soft water. Nitrates (from fertilizer) in water pose immediate threats to

children under three months of age because of the production of

methemoglobulin.

Sulfur will be a problem to some people.

City water today contains from 100 to 10,000 times as many synthetic

compounds as natural spring water. Examples of gross water contamination

include

Times Beach, Missouri, with dioxin-contaminated oil used 20 years ago, the Love

Canal area of Niagara Falls, NY, Waterbury, CT, and Middleboro, KY. In the

US, some 80,000 pits and lagoons that hold toxic wastes ranging from carbon

tetrachloride to discarded mustard-gas bombs have been reported.

In the early 1980s, California, New York, New Jersey, Arizona, Nova Scotia,

and Pennsylvania condemned dozens of public water supply wells because of a

trichloroethylene pollution. Leaking fuel tanks contaminated Kansas public

water supplies in 1981. Officials in New Mexico identified 25 cities where

hydrocarbons and solvents contaminated the groundwater. Analysis of New Orleans

drinking water revealed the presence of 13 halogenated hydrocarbons.14

Fifty-five percent of the water treated in municipal plants is from homes,

and the remainder from industry (an important source of contamination). Over

half of the total volume of industrial wastes comes from paper, organic

chemical manufacturing plants, petroleum companies, and steel manufacturing

plants.

The major pollutants are chemical byproducts, oil, grease, and radioactive

waste. Agricultural wastes include livestock and toxic chemicals (pesticides,

herbicides, fertilizers) that run off from the farm lands into rivers, lakes,

and groundwater.15

Inorganic compounds contributing to pollution include arsenic, cadmium,

chromium, copper, manganese, mercury, silver, and selenium. Asbestos may be a

significant factor because over 200,000 miles of asbestos cement pipes are in

use in the US.16

In 1965, a serious problem related to drinking water existed in

approximately 40% of patients hospitalized for a diagnostic therapeutic program

of

comprehensive environmental control; today, this figure is 80%. Patients

susceptible to water contaminants exhibit multiple sensitivities. Many patients

seen in

the ECU with their unique metabolic individuality are even found to be

intolerant of specific spring waters. Some have difficulty with waters

containing

high levels of sodium, calcium, or bicarbonates. If the reactions to specific

water contaminants are undiscovered, evaluation of other incitants,

including food and chemical testing, may be inaccurate. It is, therefore,

necessary

to find safe water before proceeding with other testing in severely sensitive

persons.

Food Contaminants

The study of food sensitivity is complicated by the use of food additives,17

preservatives, and dyes in the manufacturing and processing of commercially

available food products. This is forcing us to define more clearly the nature

of the incitants in foods and water. Bell18 has reported urticaria,

hyperactivity, and immunologic changes after food-contaminant exposure in

sensitive

persons. Urticaria has been described with several additives such as

p-hydroxybenzoic acid propylester, benzoic acid, sodium benzoate, and indigo

carmone.19 A casual role in the provocation of vascular alterations is played

by

tartrazine azo dyes and salicylates.20 Sodium nitrite and sodium glutamate have

been found to trigger migraine in susceptible patients. Sulfur dioxide and

sodium salicylate can provoke asthmatic reactions, and aspirin additives and

aspirin-like food contaminant dyes may trigger urticaria, angioedema,

bronchoconstriction, and purpura. Severe gastrointestinal disorders have been

associated with sensitivities to aniline, commonly found in rapeseed oil.

Home Contamination

Indoor air pollution has spawned a multitude of sensitivities to

chemicals.21-24 Numerous hygienic products may be noxious to the chemically

susceptible

person, including a wide variety of cosmetics (particularly those containing

glycerin or propylene glycol), perfumes and hair products, such as dyes,

creams, sprays, soaps, shampoos, and contact solutions. Chemicals in textiles,

including synthetic acrylic fibers, polyester spin finishes, the epoxy resins,

and synthetic clothing, may act as environmental antigens and are widespread.

Many household cleaning products, particularly those containing

formaldehyde, phenols, and chlorine have been shown to be hazardous for many.

Chemicals

contained in wood preservatives (pentachlorophenols) are environmental

incitants capable of triggering a variety of symptoms. Others report problems

with

formaldehyde-containing pressed board, carpets, plywood, and petrochemical

contaminants. Pesticides and fossil fuels (oil, gas, and coal) are the number

one offenders in homes.

Occupational Contamination

Because many workers’ symptoms improved during evening hours and weekends,

heretofore " safe " occupations must be re-evaluated for potential hazards.25-27

Automobile factory workers exposed to polyurethane foam have been shown to

be at significant risk, particularly because this industry uses a sizable

number of chemicals, such as chrome, rubber, nickel, and isocyanates in spray

paints, capable of triggering sensitivities. Occupation-related respiratory

diseases are common among grain elevator workers and farm workers, who can

demonstrate symptoms ranging from rhinitis to asthma. Abnormal responses may

also

be seen in persons who work with pesticides, herbicides, and farm equipment,

as well as in persons employed in carpentry (contact sensitivities to woods),

painting (severe respiratory symptoms), bricklaying (chemicals such as

cobalt), hair care (variety of hydrocarbons), baking, photography, and film

processing.

The list of occupations in which exposures to potentially hazardous

chemicals may occur seems endless. What is remarkable, however, is the extent

to

which seemingly safe occupations are fraught with risks; for example, a

chemically triggered reaction may occur in a concert violinist because of

contact with

rosin.28 Over the past three years, some 60 reports have associated

dermatitis with chemical sensitivity in the work environment, including the

latex

surgical gloves and hand scrub solutions used by surgeons. Against the backdrop

of present research, it seems clear that a virtually infinite number of

occupations contain dangers for the susceptible person. Data clearly reveals

the

necessity of environmental control for the evaluation and treatment of such

occupational sensitivities.

Mechanisms of Sensitivity

Our understanding of the mechanisms involved in chemical sensitivity is

becoming clearer. Pollutant injury of the lungs or liver leads to free radical

generation and subsequent disturbances at the cellular, subcellular, and

molecular levels. This reaction can be either immunologic or nonimmunologic

through

the enzyme detoxification systems. Then, vascular-autonomic nervous system

dysfunction occurs with a myriad of end-organ responses.29-30

Immunologic

Type I hypersensitivity is usually mediated through the IgE mechanism on the

vessel wall. Classic examples are angioedema, urticaria, and anaphylaxis

caused by sensitivity to pollen, dust, mold, food, or chemicals, such as

toluene

diisocyanate.31 Of the patients seen at the EHC-Dallas, 10% seem to fall

within this category.

Type II cytotoxic damage may occur with direct injury to the cell. A

clinical example is the patient exposed to mercury.32 Twenty percent of the

patients

seen at the Dallas ECU fall into this category.

Type III immune complexes of complement and gamma globulin may damage the

vessel wall. A clinical example is lupus vasculitis.33-34 Numerous chemicals,

including procainamide and chlorothiazide, are known to trigger the

autoantibody reaction of lupus, and other chemicals have been shown to trigger

the

autoimmune response.

Type IV cell-mediated immunity occurs with triggering of T-lymphocyte.

Numerous chemicals, such as phenol, pesticides, and organohalide,35 as well as

some metals, will also alter immune responses, thus triggering lymphokines

giving the type IV reactions. Clinical examples36-38 are polyarteritis nodosa,

hypersensitivity angiitis, Henoch-Schonlein purpura, and possibly Wegener’s

granulomatosis. A recent study done at the Dallas ECU on 104 proven chemically

sensitive (70 vascular, 27 asthmatic, and 7 rheumatoid) persons comparing them

with 60 normal controls showed that those manifesting a chemical sensitivity

through their vascular tree had a standard deviation suppression of greater

than four of the suppressor T-cell population.27 Clearly, the larger portion

of our patients fall into the type III and type IV categories.

Nonimmune Enzyme Detoxification

Nonimmune triggering of the vessel wall may occur. Complement may be

triggered directly through the alternate pathway by molds, foods, or toxic

chemicals. Mediators such as kinins and prostaglandins may also be directly

triggered.

These reactions then cause vascular spasm with resultant hypoxic release of

lysozyme, which further accelerates the cycle with more spasm and hypoxia.

Eventually, end-organ failure will occur.

Triggering of the enzyme detoxification systems also may occur in any organ

but more frequently in the liver and respiratory mucosa. Foreign compound

biotransformations vary greatly depending on genetic and environmental factors

such as age, sex, nutrition, health status, and the size of the dose. For

example, phenol may be excreted by the following pathways: phenyglucuronide

(50%), potassium phenylsulfate (40%), guinol (10%), and catechol (1%). The

metabolism of foreign compounds usually occurs in the microsomal fraction

(smooth-muscle reticulum) of liver cells. A few biotransformations are

nonmicrosomal

(redox reactions involving alcohols, aldehydes, and ketones). The four basic

biotransformation categories are oxidation, reduction, degradation, and

conjugation. Because the first three are the same for nutrients, food problems

are

important in clearing and treating chemical sensitivity. The fourth category

appears unique for the catabolism of foreign compounds using amino acids and

their derivatives with peptide bonds and carbohydrates and their derivatives

with glycide for bonds. Simpler compounds like sulfate and acetate are

occasionally involved in conjugation linkage of ester bonds. Activated

conjugated

compounds and specific enzymes are often coupled with coenzymes from which they

can be transferred to the foreign compound.30

Diagnosis

The diagnosis of chemical sensitivity can now be made with a combination of

history; physical examination; immune tests, including IgE, IgG, complements,

and T and B lymphocytes with subsets; blood levels of pesticides, organic

compounds, and heavy metals (intracellular); and, occasionally, brain function

tests. Challenge tests are the cornerstone of confirmatory diagnosis. These

may be accomplished through oral, inhaled, or intradermal challenges. Care

should be taken to rule out inhalant problems with pollen, dust, and molds.

Food

sensitivity must be considered, because it occurs in approximately 80% of

persons with chemical sensitivity. Water-contaminant sensitivities must also be

determined because 90% of persons with chemical sensitivity have

water-contaminant sensitivity. This can be checked by placing the patient on

chemically

less contaminated water (charcoal-filtered, distilled, or glass-bottled

spring water) for four days, with rechallenge with the patient’s usual

drinking

water.

Patients often know the location and time of the onset of symptoms. They may

report sensitivity to the odor of gasoline, perfumes, new paints, car

exhausts, gas stoves, fabrics, clothing or carpeting stores, chlorine and

clorox,

or cigarette smoke. Other symptoms can range from fatigue to classic end-organ

failures. Physical findings frequently are vascular in nature and include

edema, petechiae, spontaneous bruising, purpura, and peripheral coldness and

arterial spasm. Frequently, flushing, acne (adult), and a yellowness of the

skin without jaundice occur. Chronic recurring signs of any organ system with

chronic nonspecific inflammation, such as vasomotor rhinitis, colitis,

cystitis, and vasculitis, may occur. Laboratory findings are often not

specific:

sedimentation rates may increase or liver enzymes may be mildly elevated,

positive C-reactive proteins and abnormal complement levels can be found,

T-cell

levels may also be depressed and blastogenesis impaired. Finally, a number of

patients will be found to have abnormal delayed hypersensitivities as elicited

by delayed skin tests. As mentioned before, patients with T-cell

abnormalities may have a suppressor-cell population that is more than four

standard

deviations lower than normal controls. Blood levels of pesticides are now

available. Table 1 lists our findings in more than 200 chemically sensitive

patients.

Table 2 lists the volatile organic chemicals found in 114 patients studied

from 1983 to 1986.

 

Table 1

Blood Levels of Pesticides Found in 200 Chemically Sensitive Patients

Pesticide

 

Serum Levels

 

Distribution (%)

 

Length of Exposure1

DDT and DDE

 

0.3 ppb to 300 ppm

 

62.0

 

Chronic

Hexachlorobenzene

 

²

 

57.5

 

²

Heptachlor epoxide

 

²

 

54.0

 

²

Beta-BHC

 

²

 

34.0

 

²

Endosulfan I

 

²

 

34.0

 

²

Dieldrin

 

²

 

24.0

 

²

Gamma-Chlordane

 

²

 

20.0

 

²

Heptachlor

 

²

 

12.5

 

²

Gamma-BHC

 

²

 

9.0

 

²

Endrin

 

²

 

5.5

 

²

Delta-BHC

 

²

 

4.0

 

²

Alpha-BHE

 

²

 

3.5

 

²

Mirex

 

²

 

2.0

 

²

Endosulfan II (1983)

 

²

 

1.5

 

²

1Time from exposure to testing, in days.

Table 2

Volatile Organic Chemicals Found in 114 Patients

Chemicals

 

Serum Levels

 

Distribution (%)

 

Length of Exposure1

Tetrachloroethylene

 

0.3 to 500 ppb

 

83.1

 

Chronic

Toluene

 

²

 

63.2

 

²

Xylene

 

²

 

59.7

 

²

1,1,1-Trichloroethane

 

²

 

50.5

 

²

Dichloromethane

 

²

 

49.7

 

²

Ethylbenzene

 

²

 

39.2

 

²

Chloroform

 

²

 

36.9

 

²

Benzene

 

²

 

23.4

 

²

Styrene

 

²

 

22.0

 

²

Dichlorobenzene

 

²

 

10.5

 

²

Trichloroethylene

 

²

 

8.6

 

²

Trimethylbenzene (1984-1985)

 

²

 

3.2

 

²

1Time from exposure to testing, in days.

Unfortunately, organophosphate levels are only positive within 24 hours

after exposure. Blood levels for pentachlorophenol and organic solvents like

hexane and pentane are now available, as are herbicide levels. General volatile

organic hydrocarbons, such as benzene, toluene, and xylene, are found in a

large portion of chemically sensitive patients. Their presence indicates either

recent exposure or a breakdown in the enzyme detoxification system. Metals,

including lead and mercury, have been found in 10% of the patients studied.

Challenge tests can be done by the sublingual route. The efficacy of this and

intradermal challenged of foods have been well established by numerous

double-blind studies. These need to be done because 80% of the chemically

sensitive

patients are also food sensitive. Blind intradermal challenge for chemicals

can be done with terpenes, petroleum-derived ethanol, glycerine, formaldehyde,

phenol, perfume, and newsprint. Production of symptoms establishes the

chemical sensitivity. More than 200,000 intradermal challenges of chemicals

done

at the EHC-Dallas were considered positive when they met the criteria of

reproduction of signs and symptoms, wheal growth, and negative placebo

response.

Inhalation challenge is another modality for the diagnosis of chemical

sensitivity. This can be done under environmentally controlled conditions of

many

degrees. For best results, a stainless steel glass booth is used for ambient

dose challenge of any toxic chemical. More that 16,000 ambient dose

double-blind inhaled challenges of toxic volatile organic chemicals have been

done in

our center with accurate and reproducible results. Similar studies can be

done in the office; however, under these circumstances controls are more

difficult and many more placebo reactions may occur because environmentally

controlled conditions are much more difficult to obtain and patients are often

studied in the masked state.

Vitamin and intracellular mineral levels are needed to evaluate completely

the chemically sensitive person. In our center, analysis of more than 300

chemically sensitive patients from 1984 to 1985 has shown a number of vitamin

deficiencies: B6 (64%), B2 (30%), B1 (29%), folic acid (27%), vitamin C (25%),

vitamin D (24%), vitamin B3 (19%), and vitamin B12 (3%). Furthermore, of 190

chemically sensitive patients with mineral deficiencies, 88% had chromium

deficiencies, 35% sulfur deficiency, 12% selenium, and 8% zinc deficiency.

Treatment

The cornerstone of treatment for chemical sensitivity is avoidance. This

will decrease total body burden, allowing recovery of the detoxification

systems. Chemically less contaminated water may be used including spring,

distilled,

and charcoal-filtered water, but only in glass and steel containers.

Chemically less contaminated food on a rotary diet should also be used to

reduce

load and keep the patient in the nonadaptive state. As many synthetic

substances

as possible should be removed from the home, including petroleum-derived

heat, routine insecticides, synthetic carpets and mattresses, and

formaldehyde-containing substances, such as pressed board and plywood. A change

in work

areas is often needed. This can be determined by the general volatile organic

hydrocarbon blood tests. Sometimes job changes are necessary, and occasionally

the most severely sensitive patients have to leave certain polluted

geographic areas.

Injection therapy for inhalants, foods, and some chemicals such as terpenes,

perfumes, and petroleum-derived ethanol may also help alleviate a

chemically-induced hypersensitivity. These can be done daily, but usually are

given

every four to seven days. A rotary diet is also essential in treating any food

sensitivities. Vitamin and mineral supplementation is often necessary to

replace any deficiencies occurring from direct toxic damage, an increased

metabolism required for detoxification, or competition with direct absorption.

Summary

Chemical sensitivity—the adverse reaction to ambient levels of toxic

chemicals generally accepted as being subtoxic in the air, food, and

water—is now

becoming a well-recognized phenomenon. Widespread toxic chemical pollution of

our air, food, and water trigger immune and enzyme detoxification

mechanisms. This may result in adverse effects on the neurovascular, endocrine,

gastrointestinal, respiratory (including ear, nose, and throat), genitourinary,

msuculoskeletal, and dermal systems. Laboratory parameters, including total

eosinophil count, IgE, T & B lymphocytes, total serum complements, pesticide and

solvent, and general toxic volatile organic chemical blood levels, are

available

to aid in diagnosis and treatment. The most definitive means of diagnosis

are challenge tests by inhalation, oral, and intradermal exposures.

Bibliography

1. Rea WJ, Brown OD: Cardiovascular disease in response to chemicals and

foods, in Brostoff J, Challacombe (eds): Food Allergy and Intolerance. London,

Bailliere Tindall, 1987.

2. Selye N: The general adaptation syndrome and the disease of adaptation. J

Allergy 1946; 17:23.

 

3. Stokinger NE, Coffin DL: Biological effects of air pollutants, in Stern

AC (ed): Air Pollution. New York, American Press, 1968.

4. Wark K, Warner CF: Air Pollution: Its Origin and Control. New York:

Harper and Row, 1961.

5. Randolph, RG: Sensitivity to petroleum: Including its derivatives and

antecedents. J Lab Med 1952;40:931-932.

6. Stokinger HE: Ozone toxicology: A review of research and industrial

experience: 1954-1962. Arch Environ Health 1965; 110:719.

7. Rea WJ, Mitchell MJ: Chemical sensitivity and the environment. Immunology

Allergy and Practice 1982;157:21-31.

8. Rea WJ: Environmental triggered small vessel vasculitis. Ann Allergy

1977;38:245-251.

9. Jordan WP, Sherman WT, King SE: Threshold responses in

formaldehyde-sensitive subjects. J Am Acad Dermatol 1979; 1(1):4-8.

10. Meneghini C, Angelini G: Intradermal test in contact allergy to metals.

Acta Derm Venereol 1979;59-85.

11. Rea WJ, Peters D., Smiley R, et al: Recurrent environmentally triggered

thrombophlebitis. Ann Allergy 1981;47:5(1), 338-344.

12. McMillan, R: Environmental thrombocytopenic purpura. JAMA

1979;242(22):2434.

13. Peacock A: Case reports, hydralazine-induced necrotizing vasculitis. Br

Med J 1981;282:1121-1122.

14. Laseter JL, Deleon IR, Rea WJ, et al: Chlorinated hydrocarbon pesticides

in environmentally sensitive patients. Archives of Clinical Ecology

1983;2(1):6.

15. Is Your Drinking Water Safe? (EPA booklet). Washington, DC, Government

Printing Office, 1982.

16. Drinking Water and Health. The National Research Council, National

Academy of Sciences, 1977, pp. 439-477.

17. Juhlia L: Incidence of intolerance to food additives. Int J Dermatol.

1980: 19(10):548-551.

18. Bell I, King D: Psychological and physiological research relevant to

clinical ecology: An overview of the recent literature. Clinical Ecology

1982;1:15-25.

19. Lindemayer N, Schmidt J: Intolerance to acetylsalicylic and food

additives in patients suffering from recurrent urticaria. Wien Klin Wochenschr

1979;91(24):817-822.

20. Monroe EW, Schulz CI, Maize JC, et al: Vasculitis in chronic urticaria:

An immunopathologic study. J Invest Dermatol 1981;72(2):103-107.

21. Randolph TG: Human Ecology and Susceptibility to the Chemical

Environment. Springfield, IL, Charles C Thomas, 1962.

22. Gilpin A: Air Pollution, ed 2. St. Lucia, Australia, University of

Queensland Press, 1978.

23. Laseter, JL, DeLeon, IR, Rea WJ, et al: Chlorinated hydrocarbon

pesticides in environmentally sensitive patients. Clinical Ecology

1984;2(1):3-12.

24. DeBartoli M, Knoppel N, Pecchio E, et al: Measurements of Indoor Air

Quality and Comparison with Ambient Air: A Study on 15 Homes in Northern Italy.

Commission of the European Communities, Luxembourg, 1985.

25. Hjorth N: Occupational dermatitis in the catering industry. Br J Derm

1985;105:37-40.

26. Fruhamann G. Occupational asthma, new findings on work related

obstructive respiratory diseases. MMWR 1981;123(8):299-303.

27. Winslow SG: The Effects of Environmental Chemicals on the Immune System:

A Selected Bibliography with Abstracts. Oak Ridge, TN, Toxicology

Information Response Center, Oak Ridge National Laboratory, 1981, pp 1-36.

28. Fisher AA: Allergic contact dermatitis in a violinist: The role of

abietic acid—a sensitizer in rosin (colophony)—as the causative agent.

Cutis

1981;27(5):466,468,473.

29. Rea, WJ, Johnson AR, Youdim S, et al: T- and B-lymphocyte parameters

measured in chemically sensitive patients and controls. Archives of Clinical

Ecology 1986;14(1):11-14.

30. Reeves AL (ed): Toxicology Principles and Practices. New York, John

Wiley and Sons, 1980, pp 16-28.

31. Butcher, BJ, Jones RN, O’Neill CE, et al: Longitudinal study of workers

employed in the manufacture of toluene diisocyanate. Am Rev Resp Dis

1977;116(3):411-422.

32. Gaworski CL, Sharma RP: The effects of heavy metals on (3H) thymidine

uptake in lymphocytes. Toxicol Appl Pharmacol 1978;46(2):305-313.

33. Katz P: Hypersensitivity vasculitis. American Family Physicians

1982;26(1):171-175.

34. Tumulty, PA: Systemic lupus erythmatosus, in Wintrobe MM, Thorn GW,

Adams RD (eds): Harrison’s Principles of Internal Medicine. New York,

McGraw-Hill, 1970, pp 1962-1967.

35. Winslow SG: The Effects of Environmental Chemicals on the Immune System:

A Selected Bibliography with Abstracts. Oak Ridge, TN, Toxicology

Information Response Center, Oak Ridge National Laboratory, 1981, pp 1-36.

36. Zeek PM: Periarteritis nodosa and other forms of necrotizing angiitis. N

Engl J Med 1953; 248:764.

37. Rea WJ: Environmentally triggered small vessel vasculitis. Ann Allergy

1977; 38:245-251.

38. Nour-Elden R: Uptake of phenol by vascular and brain tissue. Microvasc

Res 1970;2:224-227.