Chemical Exposure and Toxic Responses

Stephen K. Hall

• Publisher: CRC Press
• Year: 2020
• eBook ISBN:
  9781000157604
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

Providing material for practitioners and students alike, Chemical Exposure and Toxic Responses is a clear and straightforward presentation of industrial toxicology. Exposure to toxic chemicals is of major concern to health professionals. In recent years, the scope and importance of hazardous materials toxicology has expanded and now impacts financial institutions, government, private corporations, and many other organizations as well. Chemical Exposure and Toxic Responses presents the myriad health implications of hazardous chemicals in a single source. This book is organized so that readers can proceed from a general perspective on the problem of chemical exposure and toxic responses to an understanding of toxicology and a method of inquiry. Written for anyone who needs practical toxicological information, the book compactly and efficiently presents the scientific basis of toxicology as it applies to the workplace. It covers the diverse chemical hazards encountered in the work environment and provides a practical understanding of these hazards for those charged with protecting the health and well being of people at work. Chemical Exposure and Toxic Responses consists of three parts: Part I establishes the general principles of industrial toxicology; Part II addresses specific effects of toxic agents on specific physiological organs and systems; and Part III is devoted to the evaluation of hazards in the workplace.

Part I: General Principles

1

Basic Concepts of Exposure and Response

Robert B. Forney, Jr.

CONTENTS

Introduction

Dose-Response Relationships

Chronicity of Exposure

Types of Toxic Reactions

Structural Considerations

Membranes

Biochemical Considerations

Ionization

Partition Coefficient

Absorption

Mechanisms

Routes

Dermal

Gastrointestinal

Respiratory

Distribution

Volume of Distribution

Storage

Blood-Brain Barrier

Placental Barrier

Elimination

References

INTRODUCTION

The study of the interactions which occur between a toxicant and an individual may be divided into two parts. The mechanisms of injury and the signs and symptoms associated with it are the “dynamics” of the toxicant’s action. However, before such dynamics may occur, a toxicant must first accumulate at a target organ or cell in adequate concentration to exert its effect. The study of the transit of a toxicant into and through the body, of its metabolism and excretion, and of the rates at which these events occur is called “toxicokinetics”.

Observed variability in response to toxic agents can be attributed to either dynamic or kinetic factors. Dynamic differences in response are due to the dose; host factors such as age, genetic background, and disease state; and environmental factors such as the form of the agent, atmospheric conditions, and the presence of other agents. Kinetic differences can be attributed to the route and chronicity of exposure, and the rates and extent of absorption, distribution, biotransformation, and excretion. These latter differences affect the “dose” at a target cell, and therefore, the outcome of the exposure. Although toxic effects are often listed for agents without reference to dose, it is the dose and its individual-specific kinetics which make the difference.

Until recently, it was believed that the skin, oropharynx, and respiratory system effectively prevented the entry of toxic agents into the body. Now it is known that toxicants can pass through these barriers, even though they may do so at a very slow rate. Generally speaking, inhalation is the most rapid, and dermal is the least rapid, route of entry. But the rate of entry is determined by the form of the agent, its dose, and the integrity and saturability of the epithelium involved.

In many cases, the route of absorption will determine not only the rate of accumulation but also the metabolism and effects of an agent. Ingestion exposes the gastrointestinal (GI) tract to direct contact with the parent toxicant. It also exposes the agent to the acid, pepsin, and bacterial flora of the GI tract. Unlike other routes of entry, all of the blood supply from the GI tract must transit the liver before entering the general circulation. As a result, much more of the agent is exposed to metabolic alteration before circulating to target organs.

The major routes of entry are the dermal, gastrointestinal, and respiratory. The relative importance of a given route will depend upon the chemical form of the agent, and the individual and environmental conditions (ventilation, protective barriers, other agents, etc.) present during the exposure.

Once an agent has entered the body, it is distributed to target sites of action — sites of metabolic change and excretion. The circulatory system is of prime importance, because it transports both water and lipid soluble agents via the plasma and the proteins contained within the plasma. The proteins bind some toxicants for release at different points within the system. Changes in binding, as well as changes in the target points for storage, action, metabolism, or elimination, will alter the toxic effects which result from the individual having been exposed.

Finally, the chronicity of the exposure must be considered. Acute (single or short duration exposure), subacute (several weeks), and chronic (months or years) each present further complicating factors which need to be considered before an exposure outcome can be accurately predicted.

DOSE-RESPONSE RELATIONSHIPS

The relationship between the dose of a toxicant and the resulting effect is the most fundamental aspect of toxicology. Many believe, incorrectly, that some agents are toxic and others are harmless. In fact, determinations of safety and hazard must always be related to dose. This includes a consideration of the form of the toxicant, the route of exposure, and the chronicity of exposure.

FIGURE 1.1 Adsorption and distribution of chemicals in the body.

A dose-response relationship can be constructed for each type of effect an agent is capable of producing. These curves can be plotted for populations (the Y axis expressing epidemiological data in percentages) or for individuals (the Y axis expressing a quantitative measure of response, e.g., beats per minute for change in heart rate).

Some terms frequently used in describing the dose-response relationship of a given toxicant are given in Table 1.1.

CHRONICITY OF EXPOSURE

There are four classifications of toxicant exposure by duration or chronicity:

Classification	Duration of Exposure
Acute	Less than 24 h
Subacute	1–30 days
Subchronic	1–3 months
Chronic	More than 3 months

TABLE 1.1 Terms Commonly Used To Describe the Dose-Response Relationship of Toxicants

The duration of exposure may be the most important determinant of the dose, and therefore, of the agent’s toxicity. Acute exposure often is by a single dose, but repeated exposures still qualify as long as they occur within a single 24-h period. Repeated doses will lead to accumulation if the interval of exposure is less than the time required for elimination. The rate of accumulation is increased as the exposure interval relative to the elimination rate is decreased.

FIGURE 1.2 Illustrations of the concepts of “potency” (“A” is more potent than “B”), “efficacy” (“D” is more efficacious than “C”) and “probits” (compare the probit scale on the left with the % response scale on the right.)

Occupational exposures are often chronic, with “exposure holidays” occurring when the worker is away from the workplace. An exposure may be chronic without representing a hazard to the individual if the dose is low enough, or if the interval of exposure is long enough. Improvements in the use of protective barriers and monitoring devices have generally reduced hazards.

Airborne toxicants may have reference ranges established for aa index of their hazard. “Threshold Limit Values” (TLVs, published by the American Conference of Governmental and Industrial Hygienists) take chronicity into account. Three chronicity ranges are used in combination:

TLV	Meaning	Duration Covered
TWA	Time Weighted Average	Average concentration safe for 8-h working day
STEL	Short Term Exposure Limit	Average concentration safe for 15-min period
Ceiling	Maximum safe concentration	Single moment concentration

TYPES OF TOXIC REACTIONS

Not all of the effects produced by toxicants are harmful. The harmful ones may be described by one or more types of reactions and are given in Table 1.2.

STRUCTURAL CONSIDERATIONS

Membranes

Davson and Danielli first postulated the basic bimolecular lipid leaflet structure of cell membranes. With few exceptions (occurring only in some specialized plant and animal species), this basic nature of membranes is consistent. The epithelial cells lining the GI and respiratory tracts have membranes of this nature.

TABLE 1.2 Types of Toxic Reactions

Reaction Type	Description
Allergic	Requires previous sensitization by the agent or by another substance structurally similar to the agent
Idiosyncratic	Genetically determined abnormal response
Local	Response at the site or sites of contact with the agent
Systemic	Response following absorption and distribution of agent
Immediate	Response develops rapidly after single exposure
Delayed	Response which develops after a “latent” period (e.g., cancer)
Reversible	Tissue has capacity for regeneration from injury
Irreversible	Tissue injury is such that regeneration is not possible
Additive	Two or more agents exerting combined effect which is equal to the sum of each individual effect
Synergistic	Two or more agents exerting combined effect which is much greater than the sum of each individual effect
Antagonistic	Two or more agents exerting combined effect which is much less than the sum of each individual effect; this may be due to offsetting effects, blocking effects, inactivation or change in absorption, distribution or elimination
Tolerance	State of diminished effectiveness of a toxicant resulting from prior exposure; tolerance may be due to either dynamic or kinetic alterations in responsiveness

Two mirror image, lipid leaflets form opposing sides of the membrane, giving it an average width of 75 Å. Phospholipids and cholesterol are the predominant lipids found with spingolipids and other minor components. For this reason, lipid...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Preface
• Editor
• Contributor
• Table of Contents
• Part I: General Principles
• Part II: Toxic Responses
• Part III: The Work Environment
• Index