Chemical Hypersensitivity and the Allergic Response

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Chemical Hypersensitivity and the Allergic Response

http://www.aehf.com/articles/article36.html

by William J. Rea, M.D.

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.

 

[You will need to go to the url to view the following Tables

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Table 1 Blood Levels of Pesticides Found in 200 Chemically Sensitive

Patient

1Time from exposure to testing, in days.

 

Table 2 Volatile Organic Chemicals Found in 114 Patients

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.

 

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