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Laboratory Safety Program

Basic Toxicology


Contents:
  1. Introduction to Toxicology
  2. Toxicity Tests
  3. Dose-Response Relationship
  4. Types of Toxic Hazards

i. Introduction to Toxicology
 
Toxicology is defined as the study of chemical or physical agents which interact with biologic systems to produce a response in the organisms. Toxicity is the relative ability of a substance to cause injury to biologic tissue. Given the broad range of toxicities any substance might eventually invoke in an organism, it is easy to understand the wisdom of Paracelsus (1493-1541) when he said, All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.
 
The dose determines if the effects of any substance are toxic, non-toxic, or beneficial. Dose is the quantity of a substance to which an organism is exposed. In toxicological studies, the dose given to test animals is expressed in terms of quantity administered:
 
• Per unit weight, usually expressed as milligrams of substance per kilogram of body weight (mg/kg).
 
• Per area of skin surface, also expressed as mg/kg.
 
• Per unit volume of air inhaled, usually expressed as parts of vapor or gas per million parts (ppm) of air by volume. Solids would be expressed as milligrams of material per cubic meter of air (mg/m3). Inhaled doses can also be expressed by time.
 
ii. Toxicity Tests
 
The design of any toxicity test incorporates selection of:
 
• A test organism, which can range from cellular material and selected strains of bacteria through higher order plants and animals.
 
• The response or biological endpoint, which can range from subtle changes in physiology and behavior to death.
 
• An exposure or test period.
 
• Dose or series of doses.
 
The objective is to select a test species that is a good model of humans, a response that is not subjective and can be consistently determined, and a test period that is relatively short. Often tests must be selected that yield indirect measurements or responses that supposedly correlate well with the response of interest — for example, determining carcinogenic potential by measuring mutagenic potential.
 
 
iii. Dose-Response Relationship
 
A particular toxicity test exhibits a dose-response relationship when there is a consistent mathematical relationship between the proportion of individuals responding and a given dose for a given exposure period. For example, the number of mortalities increases as the dose of chemical given to a group of organisms increases.
 
Measurement of Response
Different species of test organisms differ in how they respond to a specific chemical. In addition, there are variations in response to a given dose within a group of test organisms of the same species. Typically, this intraspecies variation follows a normal (Gaussian) distribution when the number of organisms responding is plotted against the degree of response for a given dose.
 
Several basic relationships can be readily identified from the plots. A dose is often described as either a lethal dose (LD) in a test where the response is mortality, or effective dose (ED) in a test where the response is some other observable effect.
 
Constructing an ultimate dose-response curve enables the identification of doses which affect a given percent of the exposed population, e.g., the LD50 is that dose which is lethal to 50 percent of the test organisms.
 
Dose-Response Terms
The National Institute for Occupational Safety and Health (NIOSH) defines a number of dose-response terms:
 
• Lethal dose fifty (LD50) calculated dose of a substance which is expected to cause the death of 50 percent of an entire defined experimental animal population.
 
• Lethal dose low (LDLo) The lowest dose of substance introduced by any route other than inhalation which has been reported to have caused death in humans or animals.
 
• Toxic dose low (TDLo): The lowest dose of a substance introduced by any route other than inhalation, over any given period of time, and reported to produce any toxic effect in humans or carcinogenic, neoplastigenic, or teratogenic effects in animals or humans.
 
• Toxic concentration low (TCLo) The lowest concentration of a substance in air to which humans or animals have been exposed for any given period of time that has produced any toxic effect in humans or carcinogenic, neoplastigenic, or teratogenic effects in animals or humans.
 
• Lethal concentration low  (LCLo): The lowest concentration of a substance in air which has been reported to have caused death in humans or animals.
 
Use of Dose-Response Relationship
Comparing the LD50 of chemicals in animals gives a relative ranking of acute toxicity of each. For example, DDT (LD50 for rats = 113 mg/kg) would be considered more toxic than ethyl alcohol (LD50 for rats = 1400 mg/kg). Using this LD50 (mg/kg) and multiplying by 70 kg (average mass of human) gives a rough extrapolation to humans, assuming they are as sensitive as the species tested to the substance tested.  However, LD50 serves only as a rough estimate of one aspect of the toxic potential of a substance.

TOXICITY RATING CHART (oral)
Toxicity Rating    Oral Acute LD50 for Rats
Extremely toxic        1 mg/kg or less (e.g., dioxin, butulin toxin)
Highly toxic        1 to 50 mg/kg (e.g., strychnine)
Moderately toxic    50 to 500 mg/kg (e.g., DDT)
Slightly toxic  0.5 to 5 gm/kg (e.g., morphine)
Practically nontoxic       5 to 15 gm/kg (e.g., ethyl alcohol)

Shortcomings of Dose-Response Data
Several shortcomings must be recognized in utilizing LD50 dose-response data for assessing the overall toxicity of a compound. One is that an LD50 is a single value and does not indicate the shape of the curve — that is, what the dose-response interval is, which is as important as how high or low the LD50 is. Thus, comparing these values can give the wrong impression.
 
Second, the LD50 measures only acute toxicity. The full range of toxicity testing includes subacute, chronic, carcinogenic and reproductive toxicity, amongst others. Therefore, while useful, the LD50 must be used with considerable discretion and caution.
 
Routes of Exposure
There are three main pathways for substances to enter the body:
 
·      Absorption (through contact with skin, and eyes)
·      Inhalation
·      Ingestion
 
The primary function of the skin is to act as a barrier against entry of foreign materials into the body. If this protective barrier is overcome, toxic chemicals enter. The barrier is greatly diminished by lacerations and abrasions. Also, many organic solvents greatly increase the permeability of the skin to materials that would otherwise not pass through it. Another factor is that the skin provides a large surface area for contact with toxic agents.
 
Inhalation is the most rapid route, immediately introducing toxic chemicals to respiratory tissues and the bloodstream. Once admitted to the blood through the lungs, these chemicals are quickly transported throughout the body.
 
Health hazards to personnel from ingestion of materials are a lesser concern than skin and respiratory hazards. The number of substances that can be ingested are limited — that is, it is difficult to swallow vapors and gases.
 
iv. Types of Toxic Hazards
 
Systemic Poisons - chemical agents which act on specific target organs or organ systems.
 
Asphyxiants —   agents which deprive the tissues of oxygen, a condition called anoxia. This group is divided into simple and chemical asphyxiants. The simple asphyxiants act by diluting or displacing atmospheric oxygen, which lowers the concentration of oxygen in air.
 
Chemical asphyxiants act in one of two ways. Some prevent the uptake of oxygen in the blood. Carbon monoxide, forexample, interferes with the transport of oxygen to the tissues by strongly binding with hemoglobin to form carboxyhemoglobin, which leaves inadequate hemoglobin available for oxygen transport.
 
A second type of chemical asphyxiant does not permit the normal oxygen transfer either from the blood to the tissues or within the cell itself. Hydrogen cyanide is an example of this type.
 
Irritants  —  materials that cause inflammation of membranes. The mechanism of irritation is either by corrosive or drying action, and may affect the eyes, skin, respiratory membranes, or gastrointestinal tract. The irritant must come in direct contact with the tissue to cause an inflammation reaction.
 
Allergic Sensitizers  —   sensitization to a chemical involves immune mechanisms. When a foreign substance called an antigen enters body tissue, it triggers production of antibodies, which react with the antigen to make it innocuous. Upon first exposure to a specific chemical, there are no antibodies in the body. After subsequent exposures, the concentration of antibodies increases until a threshold is reached. At this point, the antibody level is high enough that upon exposure to the chemical the antigen- antibody reaction, also called an allergic reaction, is severe enough to manifest itself as one or more symptoms. The body has become “sensitized” to that chemical.
 
Carcinogens   —   a substance that is known or suspected to cause cancer in an organism . The following characteristics apply to carcinogens:
 
• Chemical carcinogens have distinct mechanisms compared to other toxic agents. The biologic effect is persistent, cumulative, and delayed, and repeated doses can be more effective than large doses.
 
• They are defined by their ability to induce neoplasms. An organism can respond to a carcinogen by: 1) an increase in the incidence of one or more types of tumors compared to controls; 2) development of tumors not seen in controls; 3) the occurrence of tumors earlier than controls; and 4) an increase in the number of tumors in individual animals compared to controls.
 
• Carcinogens are diverse chemical (and physical, e.g., ionizing radiation) agents such as organic ( benzene) and inorganic (arsenic compounds) chemicals, solid-state materials, and hormones. The widely divergent properties of these chemicals appear to produce neoplasms by different mechanisms.
 
• Some react directly with DNA and as a result are mutagenic, others do not bind covalently to DNA, but produce neoplasms after the reaction with DNA.
 
Reproductive Toxins (Mutagens, Teratogens)  —   chemicals which affect reproductive capabilities, including chromosomal damage (mutations) and effects on fetuses teratogenesis). A mutagen changes a gene in a sperm or egg cell of the parent. The parent is not affected, but the offspring suffer the consequences. Teratogenesis is also manifested in offspring but differs from mutagenesis in that it results from exposure of the embryo or fetus to the agent itself.
 
Most of the information we have about reproductive hazards comes from testing animals. Most known human reproductive toxins have similar effects in laboratory animals. Therefore, we usually assume that most agents which adversely affect reproduction in animals also have the potential to harm human reproduction.
 
 
Summary
The field of toxicology is evolving at a rapid rate. Considerable strides both in terms of elucidating the mechanism of toxicity, as well as the specific effects of individual chemicals are being made. However, the vast majority of chemicals have had little, incomplete or inadequate testing done on them. Newer tests are often of greater sensitivity, thereby indicating effects at levels previously thought safe.
 
The result of our increasing knowledge is increasing caution - we see that the more we know the more we realize how little we know. The message for us is this— minimize all exposure by reducing time, frequency and concentration of exposures, and substituting less toxic materials whenever possible.
 
 
 

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Last Modified February 1, 2008