Brain tumors with restricted diffusion

LIVING WITH THE EARTH

TOXICITY AND TOXINS -Moore

Objectives

A student reading this chapter will be able to:
1. Discuss and define the concepts of toxic triangle, poison, hazardous material, and hazardous waste.
2. List and explain the various methods of absorption including diffusion, facilitated diffusion, active transport, and special processes.
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Objectives

3. Explain the processes of endocytosis including phagocytosis, pinocytosis, and receptor-mediated endocytosis.
4. Describe and discuss the major mechanisms by which toxic materials produce their adverse effects including: (1) inactivation of enzymes, (2) direct effect on cells and tissues, and (3) production of intermediate compounds or secondary action.
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Objectives

5.Describe and provide an overview of the immune system, the cellular and humoral immune system, and allergic mechanisms.
6. Discuss and describe the adverse health. effects associated with endocrine disruptors, PCBs, dioxin, lead, mercury, asbestos, and organic solvents.
TOXICITY AND TOXINS -Moore

TOXICITY AND TOXINS

Introduction

In the United States, there are currently more than 70,000 synthetic chemicals currently in commercial use, and for most of them, their toxicity is not widely known or understood.
TOXICITY AND TOXINS -Moore

TOXICITY AND TOXINS

Introduction

Since 1,000 - 2,000 new chemicals are introduced each year into our society, there is significant opportunity for untested materials to enter our environment and expose humans, wildlife, and plants to toxic effects.
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TOXICITY AND TOXINS

Introduction

A potentially toxic substance produces its adverse effect by interacting with humans (or organisms) and the environment in a relationship referred to as the toxic triangle (Fig. 5-1).
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Fig. 5-1

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TOXICITY AND TOXINS

Introduction

A poison or toxic substance does not constitute a hazard unless contact is made with the organism in a form and quantity that can cause harm.
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Hazardous Substance

A hazardous substance is defined in the Comprehensive Environmental Response Compensation and Liability Act (CERCLA) as any chemical regulated under the the following Acts:
Clean Air Act (CAA)
Toxic Substances Control Act (TSCA)
Clean Water Act (CWA)
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Toxic Substance

Toxic substances are those that:
(1) can produce reversible or irreversible bodily injury;
(2) have the capacity to cause tumors, neoplastic effects, or cancer;
(3) can cause reproductive errors including mutations and teratogenic effects;
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Toxic Substance

Toxic substances are those that:
(4) produce irritation or sensitization of mucous membranes;
(5) cause a reduction in motivation, mental alertness, or capability;
(6) alter behavior; or cause death of the organism.
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EXPOSURE AND ENTRY ROUTES

Exposure
In order for a toxic substance to produce its harmful effects on the human body, a person must first be exposed to the chemical.
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Exposure

Absorption
The passage of substances across the membranes through some body surfaces into body fluids and tissues by any of a variety of processes that may include diffusion, facilitated diffusion, active transport, or special processes.
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Exposure

Diffusion
A passive process that occurs when molecules move from areas of high concentration to one of low concentration.
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Exposure

Facilitated Diffusion
Some molecules such as amino acids and sugars require specialized carrier proteins to be transported across a membranes.
No high energy phosphate bonds such as ATP are required in this process.
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Exposure

Active Transport
In this process, ATP is required in conjunction with special carrier proteins to move molecules through a membrane against a concentration gradient (i.e., low concentration to high).
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Exposure

Endocytosis
Particles and large molecules that might otherwise be restricted from crossing a plasma membrane can be brought in or removed by this process.
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Three Major Types of Endocytosis

Phagocytosis
Pinocytosis
Receptor-mediated endocytosis
Ligands
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Routes of Entry

There are several ways in which toxic substances can enter the the body:
lungs by inhalation,
through the skin,
mucous membranes or eyes by absorption, or
gastrointestinal tract by ingestion.
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The Respiratory System

The respiratory system is composed of the nose, pharynx, larynx, trachea, bronchi, and lungs (Fig 5-2).
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Fig. 5-2

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The Respiratory System

External Respiration
The act of breathing or ventilation brings air into and out of the lungs.
Internal Respiration
The exchange of gases between blood and individual cells.
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The Respiratory System

Bronchoconstriction narrows the lumen and restricts the flow of air, other gases, and particles from reaching more delicate tissues deeper in the lung (Fig. 5-3).
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Fig. 5-3

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The Skin

The skin is the body’s largest organs consisting of many interconnected tissues covering an area of nearly 3,000 in.2 in the average adult.
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The Skin

The skin helps to:
(1) regulate body temperature through sweat glands;
(2) provide a physical barrier to dehydration, microbial invasion, and some chemical insults;
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The Skin

The skin helps to:
(3) excrete salts, water, and organic compounds;
(4) serve as a sensory organ for touch, temperature, pressure, and pain; and
(5) provide some important components of immunity.
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The Skin

The skin has two layers (Fig. 5-4):
Epidermis
Dermis
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Fig. 5-4

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The Skin

Materials may pass through the skin by:
Absorption through hair follicles or sweat glands
Breaks in the skin
Injections
Insect bites
High pressure steam or liquid
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The Gastrointestinal Tract

The gastrointestinal tract is a major route of absorption for many toxic agents including mercury, lead, and cadmium which appear in food and water.
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The Gastrointestinal Tract

The components of the GI tract include the:
Mouth
Pharynx
Esophagus
Stomach
Small and large intestine
Anus (Fig. 5-5)
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Fig. 5-5

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The Gastrointestinal Tract

Nutrients as well as toxic agents can penetrate through the epithelial cells of the villus, enter the blood and lymph vessels, and be carried to various parts of the body (Fig. 5-6).
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Fig. 5-6

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Mechanisms of Action

The harmful effects of environmental toxins are dominated by three principal mechanisms which include:
(1) the toxins influence on enzymes;
(2) direct chemical combination of the toxin with a cell constituent and;
(3) secondary action as a result of the toxins presence in the system.
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Effects of Toxic Agents on Enzymes

Holoenzyme
Apoenzyme
Cofactor
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Effects of Toxic Agents on Enzymes

Enzymes act on substrates to add or remove molecules of water, oxygen or hydrogen, or amino- or other functional groups.
Enzymes may also rearrange atoms within a molecule, or join molecules (Fig. 5-7).
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Fig. 5-7

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Effects of Toxic Agents on Enzymes

Many toxic substances have the ability to:
(1) interfere with or block the active sites of the enzyme;
(2) inactivate or remove the co-factor;
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Effects of Toxic Agents on Enzymes

Many toxic substances have the ability to:
(3) compete with the co-factor for a site on the enzyme; or
(4) altering enzyme structure directly thereby changing the specific three-dimensional nature of the active site (Fig. 5-8).
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Fig. 5-8

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The Direct Action of Pollutants on Cell Components

Strong acids, bases, and phenols can directly etch tissue
Nitrous and sulfuric acids, and ozone can oxidize cellular material
Carbon monoxide can react directly with hemoglobin and prevent the attachment of oxygen
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Pollutants that Cause
Secondary Actions

Otherwise harmless substances may cause the formation of chemicals in the body that are harmful or potentially lethal.
Fluoroacetate (rodenticide 1080) may be converted in the body to fluorocitric acid which is often lethal in small quantities.
Allergens may produce discomforting or even fatal reactions by causing the immune system to release intermediary products such as histamines.
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Immunity and Allergies

Immunity is based on the premise that certain immune cells in the body can recognize microbes, tissues and other substances that are “non-self” or foreign, and so destroy, encapsulate, or remove them.
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Immunity and Allergies

Two separate but cooperating components of the immune system are known as:
Humoral (antibody-mediated) immunity
Cellular (cell-mediated) immunity.
The responses of cellular and humoral immunity are quite different (Fig. 5-9).
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Fig. 5-9

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Immunity and Allergy

Each component of the immune system is formed in the embryonic stages from lymphocytic stem cells that appear in bone marrow (Fig. 5-10).
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Fig. 5-10

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Immunity and Allergy

The Initial Immune Response
The immune system responds to agents, cells, or substances that are foreign or non-self, are collectively called antigens.
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The Initial Immune Response

Hapten
Macrophage
Human Leukocyte Associated antigens (HLA)
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Cellular Immunity

T cells respond to a particular antigen then enlarge, divide, and give rise to clones of several subpopulations of T cells (Fig. 5-11a,b).
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Fig. 5-11a

Adapted from Tortora and Anagnostakos11 and Tortora.12

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Fig. 5-11b

Adapted from Tortora and Anagnostakos11 and Tortora.12

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Humoral Immunity

B Cells
Produce liquid proteins (humoral) known as antibodies and secrete them into the blood stream where they can travel to the affected site and carry out their destructive action (Fig. 5-12).
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Fig. 5-12a

Adapted from Tortora and Anagnostakos11 and Tortora.12

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Fig. 5-12b

Adapted from Tortora and Anagnostakos11 and Tortora.12

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The Antibody Molecule

Antibodies (also called immunoglobulins) are proteins (Fig. 5-13).
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Fig. 5-13

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The Antibody Molecule

The five major classes of antibodies known as:
Immunoglobulins
IgG
IgA
IgM
IgD
IgE.
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The Antibody Molecule

The variable regions of the antibody are created in a specific three-dimensional form that is pre-configured in the B cell clone to only one antigenic group (Fig. 5-14).
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Fig. 5-14

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Antibody Activities

The binding of an antibody with its specific antigen can activate the complement system.
The complement system enhances phagocytosis, inflammation, and cell lysis (Fig. 5-15).
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Fig. 5-15

Adapted from Tortora and Anagnostakos11 and Tortora.12

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Hypersensitivity

An exaggerated immune response to the presence of an antigen is termed hypersensitivity or allergy.
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Hypersensitivity

There are four major types of hypersensitivity reactions:
Cytotoxic,
Cell-mediated,
Immune complex
Anaphylactic (Fig. 5-16)
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Fig. 5-16

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Factors Governing Toxicity

The outcome of exposure to a toxin depends on a number of factors that may include:
The Properties of the Chemical
Concentration
Effective Dose
Bioaccumulation
Biotransformation
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Factors Governing Toxicity

The outcome of exposure to a toxin depends on a number of factors that may include:
Interactions
Synergistic
Antagonistic
Age
Exercise and Physical Stress
Health Status
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SOME SPECIFIC EXAMPLES OF TOXIC AGENTS

Endocrine Disrupters and Reproductive Health
Hormone Function
Hormones are critical in the regulation of many life processes, including sexual development, metabolic functions, development of the brain, human growth, and stress response.
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Hormone Function

Androgens
Regulate the development and maintenance of male sexual characteristics
Estrogens
Stimulate the development of female sexual characteristics
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Adverse Effects of Endocrine Disruption

(1) reduced sperm counts;
(2) precocious puberty;
(3) increase in non-Hodgkin lymphoma;
(4) marked increase in males having undescended testicles, and
(5) testicular cancer.
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What are Endocrine Disruptors?

Examples of Endocrine Disruptors
Pesticides such as DDT
Plasticizers such as phthalates and alkylphenols
PCBs, Dioxin
A variety of naturally occurring plant compounds or phytoestrogens
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Endocrine Disruptors-How Do They Work?

There are at least four different mechanisms by which endocrine disruptors can exert their adverse effects (Fig. 5-17).
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Fig.
5-17a

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Fig.
5-17b

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Reducing Exposure

Endocrine Disruptors find their way into the food supply through:
(1) ingestion of contaminated grains and grasses by livestock which then store the lipophilic chemicals in their fatty tissues;
(2) contamination of fruits and vegetables by spraying with pesticides; and
(3) leaching from plastic wrappers, plastic liners of cans, and polystyrene containers.
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Reducing Exposure

Exposure to endocrine disruptors may be reduced by:
1. Reducing or limiting ingestion of dairy products and meat high in fat where organochlorines tend to accumulate.
2. Avoiding synthetic pesticides by purchasing foods low in pesticide residues and switching to herbal or scent-based repellents.
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Reducing Exposure

3. Keeping children from vinyl toys or teething rings
4. Using detergents, and shampoos that do not contain alkylphenols such as nonoxynol and octoxynol.
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Dioxin

Dioxin is an unwanted by-product from heating mixtures of chlorine and organic compounds in industrial processes (Fig. 5-18).
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Fig. 5-18

Dioxin
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Dioxin

Dioxin slowly breaks down in the environment when it is exposed to the ultraviolet rays of the sun, otherwise, dioxin is a stable compound.
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Dioxin

Dioxin does not attach to the estrogen receptor; rather, it attaches to a receptor called the Ah-receptor, whose function is unknown.
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Dioxin

Anti-estrogenic Effects
Dioxin indirectly breaks down the body’s normal estrogen, and decreases the number of estrogen receptors available for naturally occurring estrogen.
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Dioxin Contaminations

Vietnam
Seveso Italy
Times Beach Missouri
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Dioxin

EPA Draft of Dioxin Reassessment Document in 1994
Dioxin poses increased risk for cancers, adverse reproductive and developmental effects, neurological damage from in utero exposure, endocrine disruption, and reproductive and development effects.
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Polychlorinated biphenyls (PCBs)

PCBs are chemically inert, nonflammable fluid with high plasticizing ability, and a high dielectric constant (Fig. 5-19).
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Fig. 5-19

PCB
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PCBs

In the United States from 1929 to 1977, PCBs were used in transformers, capacitors, hydraulic and heat transfer fluids, and solvents in adhesives and sealants.
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PCBs

More than 94 percent of fish collected in the U.S. show PCB residues at an average concentration of 0.53ppm.
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PCBs

Japan, 1968
Yusho (rice oil) Disease
1300 Japanese developed symptoms, which included chloracne, eye discharge, and swelling in the joints.
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PCBs

Taiwan, 1979
Yu-cheng Disease
Children at birth were observed to have abnormalities in teeth, nails and pigmentation, low birth weights, lower IQs were observed in the children as they aged.
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Lead

In North America lead has been used in agriculture in the form of lead arsenate for pesticidal use, as solder in pipes, as a solder in food containers, and as an anti-knock compound in gasoline.
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Lead

In the 1970s, both federal regulatory and legislative efforts were begun to reduce lead hazards, including the limitation of lead in paint and gasoline (Fig. 5-20).
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Fig. 5-20

Adapted from Schwartz et al.56

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Lead

The most significant sources of exposure to inorganic lead include food, water, soil and lead-based paint.
Lead may enter the body through ingestion and inhalation, while organic lead may also be absorbed through the skin.
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Lead

Lead affects the formation of blood in two distinct mechanisms:
(1) by slowing the normal maturation of red blood cells in the bone marrow, decreasing the number of red blood cells and possibly causing anemia; and
(2) lead inhibits the synthesis of hemoglobin.
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Lead

Over the past 10 years, there has been more and more evidence that lead may have serious health effects at lower exposure levels which were previously not thought to be harmful (Fig. 5-21).
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Fig. 5-21

Adapted from U.S. Congressl.53

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Effects of Lead

Lead may:
Impair fertility in both men and women
Lower sperm counts
Cause spontaneous abortions and stillbirths
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Lead

Young children are at a greater risk for elevated lead levels due to:
(1) their increased oral activity;
(2) increased ability to absorb lead;
(3) higher retention of absorbed lead and;
(4) the incompletely developed nervous system.
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Lead

A study in the Boston Suburbs documented the negative effects of lead on classroom behaviors (Fig. 5-22).
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Fig. 5-22

Adapted from Needleman and Rabinowitz.61

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Organic Solvents

Organic solvents are a group of simple organic liquids, which have the capacity to change from liquids to gases in the presence of air.
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Organic Solvents

Organic solvents are components of many products including paints, varnishes, paint removers, adhesives, glues, degreasing and cleaning agents, pharmaceuticals, plastics and pesticides.
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Organic Solvents

Solvents enter the body by ingestion from contaminated drinking water supplies, but may enter the body via skin absorption and inhalation in the shower.
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Organic Solvents

There is disturbing evidence that organic solvents, most notably the glycol ethers, cause spontaneous abortions, birth defects and childhood cancers.
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Asbestos

Asbestos is a collective term for a group of six fibrous silicate materials:
Asmolite
Chrysotile
Tremolite
Actinolite
Anthophyllite
Crocidolite
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Asbestos

Asbestos has been used in various products and processes, including building materials, brake linings, textiles and insulation, as well as floor tiles, cement and potholders (Fig. 5-23).
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Fig. 5-23

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Asbestos

Asbestos enters our water through:
Airborne settling
Leaching from asbestos-cement pipes
Dumping of effluent from mining operations
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Asbestos

Exposure to asbestos is primarily achieved through the inhalation of these tiny fibers that are suspended in the air, often getting trapped deep within the lungs.
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Asbestos

Crocidolite is more likely to produce disease than other forms of asbestos.
Asbestosis
Lung Cancer
Mesothelioma
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Asbestos

The EPA estimated that 15 million students and 1.4 million teachers and other employees are in buildings that contain asbestos.
Asbestos School Hazard Abatement Act (ASHAA) in 1984 to provide financial assistance to schools having significant asbestos problems.
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Mercury

Three Forms
Elemental mercury vapor
Inorganic mercury compounds
Organic (usually methyl) mercury (most toxic)
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Mercury

Mercury is used in the production of chlorine, for use in thermometers, batteries and fluorescent light bulbs.
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Organic Mercury

Minamata Bay Japan
Numbness of tongue, lips, and fingers
Developmental Toxin
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Elemetal Mercury

Found in dental amalgam fillings, thermometers and batteries
Hazardous only when inhaled
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Inorganic Mercury

Vaporizes at room temperature
Exposure due to inhalation or absorption
Damage to kidneys and liver, tremors, interferes with coordination
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