SAAM-6636-001: Industrial Toxicology – Winter 2019

Class 2: Basic Principles of Toxicology

1. Different Areas of Toxicology

The professional activities of toxicologists fall into three main categories: descriptive, mechanistic,
and regulatory (Fig. 2-1 in text 1).
Although each has distinctive characteristics, each
contributes to the other, and all are vitally important to
risk assessment.
1.1. Mechanistic toxicology is concerned with
identifying and understanding the cellular,
biochemical, and molecular mechanisms by which
chemicals exert toxic effects on living organisms.
 In risk assessment, mechanistic data may be very
useful in demonstrating that an adverse outcome (e.g.,
cancer, birth defects) observed in laboratory animals is directly relevant to humans.
 For example, the relative toxic potential of organophosphate insecticides in humans, rodents,
and insects can be accurately predicted based on an understanding of common mechanisms
 (inhibition of acetylcholinesterase) and differences in biotransformation for these insecticides
among the different species.
 Similarly, mechanistic data may be very useful in identifying adverse responses in experimental
animals that may not be relevant to humans.
 For example, the propensity of the widely used artificial sweetener saccharin to cause bladder
cancer in rats may not be relevant to humans at normal dietary intake rates.
 Dose–response studies suggest that such high concentrations would not be achieved in the
human bladder even after extensive dietary consumption.
1.2. Descriptive toxicology is concerned directly with toxicity testing, which provides
information for safety evaluation and regulatory requirements.
 The appropriate toxicity tests in cell culture systems or experimental animals are designed to yield
information to evaluate risks posed to humans and the environment from exposure to specific
chemicals.
 Descriptive toxicology is not divorced from mechanistic studies, as such studies provide
important clues to a chemical’s mechanism of action, and thus contribute to the development of
mechanistic toxicology through hypothesis generation.
 Such studies are also a key component of risk assessments that are used by regulatory
toxicologists.
 1.3. Regulatory toxicology has the responsibility for deciding, based on data provided by
descriptive and mechanistic toxicologists, whether a drug or other chemical poses a
sufficiently low risk to be marketed for a stated purpose or subsequent human or
environmental exposure resulting from its use.
 The Food and Drug Administration (FDA) is responsible for allowing drugs, cosmetics, and food
additives to be sold in the market according to the Federal Food, Drug and Cosmetic Act
(FFDCA).
 The U.S. Environmental Protection Agency (EPA) is responsible for regulating most other
chemicals according to:
 The Federal Insecticide, Fungicide and Rodenticide Act (FIFRA)
 The Toxic Substances Control Act (TSCA)
 The Resource Conservation and Recovery Act (RCRA)
 The Safe Drinking Water Act (SDWA)
 The Clean Air Act (CAA)
 The Clean Water Act (CWA)
 The Comprehensive Environmental Response, Compensation and Liability Act (CERCLA)
and the Superfund Amendments Reauthorization Act (SARA), more commonly called the
Superfund Act, which includes EPCRA.
 The Occupational Safety and Health Administration (OSHA) of the Department of Labor was
established to ensure that safe and healthful conditions exist in the workplace.
 The National Institute for Occupational Safety and Health (NIOSH) as part of the Centers for
Disease Control and Prevention (CDC) in the Department of Health and Human Services is
responsible for conducting research and making recommendations for the prevention of work-
related injury and illness.
 The Consumer Product Safety Commission is responsible for protecting consumers from
hazardous household substances.
 The Department of Transportation (DOT) ensures that materials shipped in interstate commerce
are labeled and packaged in a manner consistent with the degree of hazard they present.

2. Toxicology and Society

 Information from the toxicological sciences, gained by experience or research, has a growing
influence on our personal lives as well as for human and environmental health across the globe.
 Knowledge about the toxicological effects of a compound affects consumer products, drugs,
manufacturing processes, waste clean-up, regulatory action, civil disputes, and broad policy
decisions.
3. General Characteristics of the Toxic Response
 One could define a poison as any agent capable of producing a deleterious response in a biological
system, seriously injuring function or producing death.
 This is not, however, a useful working definition for the very simple reason that virtually every
known chemical has the potential to produce injury or death if present sufficiently (Paracelsus).
 Among chemicals there is a wide spectrum of doses needed to produce deleterious effects.
 This is demonstrated in the table below, which shows the dose of several chemicals needed to
produce death in 50% of treated animals (LD50).
Agent LD50, mg/kg∗
Ethyl alcohol 10,000
Ferrous sulfate 1,500
Sodium chloride 4,000
Morphine sulfate 900
Phenobarbital sodium 150
Strychnine sulfate 2
Nicotine 1
Dioxin (TCDD) 0.001
Botulinum toxin 0.00001
* LD50 is the dosage that causes death in 50% of the affected population.
 Example: How much ethanol a person weighing 70 kg must drink to be under a risk of death?
Assume 80% of the ingested ethanol is assimilated, a drink with 40% ethanol by volume, and a
density of 0.78 g/mL for ethanol.
mg
Allowed mass of ethanol = 10,000
kg
 70kg  700,000 mg  700 g assimilated
Assuming 80% assimilation, the allowed consumption =
100 g ingested
700 g assimilated   875 g ingested
80 g assimilated

Allowed volumetric consumption =

 g  100 mL beverage
875 g  0.78 mL   40 mL ethanol  2,804.5 mL  2.8 L

The effect of time here is critical.

 However, measures of acute lethality such as LD50 may
not accurately reflect the full spectrum of toxicity, or
hazard, associated with exposure to a chemical.
 For example, some chemicals with low acute toxicity may have carcinogenic, teratogenic, or
neurobehavioral effects at doses that produce no evidence of acute toxicity.
 In addition, genetic factors can account for individual susceptibility to a range of responses.
4. Classification of Toxic Agents
 Toxic agents are classified in a variety of ways, depending on the interests and needs of the
classifier.
 In this course, toxic agents are discussed in terms of their target organs (liver, kidney, etc.), use
(pesticide, solvent, food additive, etc.), source (animal and plant toxins), effects (cancer, mutation,
liver injury, etc.), and source (industry, agriculture, construction, etc.).
 The term toxin generally refers to toxic substances that are produced by biological systems such
as plants, animals, fungi, or bacteria.
 The term toxicant is used in speaking of toxic substances that are produced by or are a by-product
of anthropogenic (human-made) activities.
 Some toxicants can be produced by both natural and anthropogenic activities.
For example, Arsenic, a toxic metalloid, may occur as a natural contaminant of groundwater or
may contaminate groundwater secondary to industrial activities.
 Toxic agents may also be classified in terms of their:
 Physical state (gas, dust, liquid)
 General chemical structure (aromatic amine, halogenated hydrocarbon, etc.)
 Poisoning potential (extremely toxic, very toxic, slightly toxic, etc.).
 Biochemical mechanisms of action (e.g., alkylating agent, cholinesterase inhibitor,
methemoglobin producer)
 More general classifications such as air pollutants, occupation-related agents, and acute and
chronic poisons which can provide a useful focus on a specific problem.