Pureheart 2011-05-15 17:06:44
Causality in Illnesses Thought to Result from Toxic Exposures
Part I: Toxicology
Leslie 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
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
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
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,
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
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.