Causality in Illnesses Thought to Result from Toxic Exposures

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Causality in Illnesses Thought to Result from Toxic

Exposures

Part I: Toxicology

J. Hutchinson, M.D., M.P.H.

Sanford S. Leffingwell, M.D., M.P.H.

Litigation in matters of toxic exposures usually

hinges on proof of a causal link between exposure and

illness. We have seen a few extreme (and

unsustainable) positions taken by both plaintiffs and

defendants in litigation, as well as a larger number

of cases where degree of causation or level proof is

legitimately debatable. This article is the first in a

planned series outlining approaches useful in

analyzing the question. The series will include an

introduction to toxicology, an introduction to

epidemiology, and a discussion of exposure and risk

assessment.

I: Toxicology

Toxicology is the study of poisons or toxicants and

their adverse effects on various organs and tissues of

the body. The term " toxin " is often used as a synonym

for poison, but some specialists prefer to reserve

that name for poisons of biological origin, like snake

venom or poison ivy. With advances in imaging

technologies and in chemical measurement technologies,

the scope of toxicology is progressively broadening to

subsume more subtle, subclinical effects of toxicants.

Paracelsus was a medieval alchemist who is often

recognized as both the " father of toxicology " and the

" father of pharmacology " because of his pioneering

work in systematizing the study of effects of

chemicals and drugs. Paracelsus stated that all

substances are poisons, and that only the dose

differentiates a poison and a remedy. This notion of

dose is critical for understanding toxic effects. At

very low doses, even the most toxic chemicals known

will cause no discernable effect on humans, while at

very high doses, even essential substances like oxygen

and water will harm or kill. In between, different

amounts will cause different degrees of harm.

Exposure is a necessary but not sufficient condition

for toxicity. This may seem trivial, but we have been

astonished how often educated people overlook the

fact. Before an illness can result from poisoning,

enough of the poison must be absorbed into the body to

cause harm. The mere presence of even a very potent

poison (toxicant) in the vicinity of a person is not

sufficient: chemicals do not magically leap from

sealed containers, run out, and bite people. They can,

however, escape those containers through a variety of

mishaps and move through air, water, soil, or food to

where a person is. Analysis of how poisons move from

where they were created to where a person could be

poisoned by them will be discussed in the article on

exposure and risk assessment.

Toxic response is a function of the characteristics of

the toxicant and of the exposure. Characteristics of

toxicants that alter the response include the source,

chemical form, and physical state of the toxicant.

Arsenic provides an example of variation in toxicity

with source and also with chemical form. Elemental

arsenic may be found in high levels in the large piles

of mine tailings at current and former copper mining

and smelting sites throughout the western U.S.

Methylated arsenic (an organic chemical form of

arsenic) accumulates in exposed fish and seafood.

Generally, toxicologists consider elemental arsenic to

be much more potent than methylated arsenic in terms

of causing cancer or neurotoxicity.

Physical state refers to whether the toxicant is in

the form of a solid, liquid, or gas or vapor. An

example of the influence of physical state on toxicity

obtains from considering how vaporization of a liquid

solvent increases likelihood of inhalation, rapid

absorption into the body, and rapid onset of acute

toxic effects.

Understanding toxicology requires recognition of the

spectrum of toxic effects. The term " side effects "

usually refers to low probability adverse effects that

may occur with drugs or pharmacologic agents. In the

U.S., the FDA requires an extensive process to

determine drug efficacy and safety before marketing is

permitted. Hence, the probability of adverse effects

from use of these agents is very small. By contrast

" adverse or toxic effects " result from exposure to

chemicals that are not carefully screened for safety

before marketing (like solvents and metals used in

industrial settings.) Therefore, the probability of

adverse effects from sufficiently high exposures tends

to be much greater.

Carcinogenic (cancer-causing) effects include the

generation of any type of cancer caused by toxicant

exposure. The potential for a toxicant to cause

carcinogenic effects is assessed by observing its

ability to generate tumors in animal test systems.

Non-carcinogenic effects include all toxic effects

other than the generation of cancer.

Acute effects are adverse effects that occur

immediately or shortly after exposure to a toxicant.

Chronic effects occur after some delay or after a long

period of chronic exposure. Carcinogenic effects for

which there is characteristically a long latent period

(typically two or more decades) between exposure and

effect are included in chronic effects. Prolonged

exposures that result in overt effects only after some

time (like ongoing low-level lead exposure in drinking

water causing peripheral neuropathy after several

years) are also included in chronic effects. Beware of

confusion resulting from these homographs. Acute and

chronic refer both to duration or time of onset of

effects and to duration of exposure. Although the

words are the same, the meanings differ.

Target organs are the specific organs or tissues

adversely affected by a particular toxicant. Organs

may be more sensitive to certain poisons because of

the way the poison is distributed in the body or

because of the way the organ reacts with, responds to,

or metabolizes the poison. Mechanism of action

includes the biochemical, physiologic, and anatomic

changes caused by a toxicant that result in its

characteristic toxic effects.

Characteristics of exposure include: dose or amount

received, the temporal characteristics of the

exposure, the nature of the exposure or how the poison

was presented to the body, and receptor

characteristics. Dose for most poisons is measured as

mass (weight) of the poison or better as mass of the

poison per kilogram of body mass. The latter allows

comparisons of expected activity on animals or people

of different size. For gases or vapors, dose is

estimated as a product of the concentration of the

poison in air multiplied by the number of minutes the

person breathed the contaminated air. If a person is

breathing a constant volume of air each minute, then

the amount of poison taken into the lungs can be

doubled by either doubling the time in the same

environment or by doubling the concentration with the

same time. The product of concentration and time is

usually written Ct and expressed in mg-min/m3

[(milligrams per cubic meter) x (minutes)]. We tend to

think of all equal Ct exposures as equally toxic, but

for a variety of reasons, shorter exposures at higher

concentrations usually cause more damage.

Temporal characteristics refer to how long the

exposure continued. Acute exposures are usually a

single dose or a single period lasting from a few

seconds to as long as a day or so. In animal studies,

the amount of poison needed to kill half of the

animals, called the LD50 for lethal dose--50%, is the

toxicologic datum most commonly available for a

poison. It is determined by exposing or dosing small

groups of animals to different amounts of poison,

noting the number in each group that die, and

determining a dose that would kill half of them.

Chronic exposures extend for a substantial fraction of

the animals lifetime: the experiments can be designed

so that they are analogous to lifetime or 40-year

working-life exposures in humans.

Nature of exposure refers to such questions as whether

the chemical is pure or in a mixture, the route by

which the poison enters the body, and the physical and

chemical state of the toxicant. Receptor

characteristics include individual susceptibility

based on age, gender, or genetic make-up. Children,

for example, may be more susceptible to lung irritants

than adults owing to their small, easily-obstructed

airways.

Different types of studies yield information on toxic

responses. Animal studies provide most of our

information because we cannot ethically expose humans

to dangerous materials. The studies fall into

categories by the length of time involved, by the

animal species used, and by the illnesses or effects

(end points) that the researchers looked for. Acute

toxicity studies, yielding an LD50, are the most

common. The LD50 is the bit of information most

commonly available for substances. Acute toxicity

studies also are often useful in identifying target

organs and in providing some information on the

reversibility and duration of effects and mechanism of

action.

The term subacute studies, refers to investigations

involving repeated administration of a toxicant to

animals for two to four weeks. These studies are

particularly useful to study irreversible (and hence

cumulative) effects or the effects of accumulation of

toxicants in the body.

In subchronic studies, investigators typically

administer four to five different doses of toxicant to

animals for 90 days. These studies establish a

no-observable-adverse-effects level (NOAEL), which

will be between the lowest dose at which adverse

effects are observed and the next lowest dose. The

NOAEL is the best estimate of the threshold for injury

and is the basis for regulating non-carcinogens.

Carcinogenicity bioassays require administering the

toxicant to groups of animals (usually rats and mice)

to determine the number of tumors produced at each

dose level tested. To be designated a proven animal

carcinogen, a toxicant must cause tumors in two

species.

Mutagenicity studies employ a wide variety of methods

to determine adverse effects or alterations in the

genetic material of cells. Mutations in somatic

(non-reproductive) cells could cause adverse effects

(like cancer) in the affected organism. Mutations in

germinal cells (ova and sperm) may be passed on to

subsequent generations.

Chronic non-carcinogenic effects studies administer

toxicant to animals for an entire lifetime (typically,

two years for rats and mice.) Chronic non-carcinogenic

effects may be significant when a toxicant has a long

half life in the body or when it has irreversible

effects (and hence cumulative effects with ongoing

exposure.)

Multi-generational reproductive and developmental

effects studies continuously expose three generations

of male and female animals to toxicant throughout

gestation, lactation, development, and reproduction.

Reproductive success of each generation is assessed.

Necropsy evaluations of the first group of offspring

of each generation and half of the pregnant females

after each mating detect embryologic malformations,

the number of embryos, and abnormalities of

implantation or fetal development. Detection of

teratogenic effects or adverse effects on female or

male reproductive functions or capacity may be further

evaluated by more specialized studies.

Human studies provide the information most relevant to

evaluating human health risks from toxicant exposures.

Human data come primarily from two sources:

environmental or occupational epidemiologic studies

and case reports. Both types will be discussed at

greater length in the second article in this series.

Environmental and occupational epidemiologic studies

are done to observe the effects of unplanned exposures

on groups of people. Case reports describe the

clinical recognition, evaluation, and treatment of one

or a few cases of poisoning resulting from exposures

to particular toxicants.

Continue to Part II - Epidemiology by Clicking Here

J. Hutchinson, M.D., M.P.H.

Sanford S. Leffingwell, M.D., M.P.H.

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