FUNDAMENTAL AND APPLIED TOXICOLOGY 3 4 , 1 - 4 (1996)
ARTICLE NO. 0 1 6 9
COMMENTARY
The Phoenix of Modern Toxicology
DENNIS V. PARKE'
School of Biological Sciences, University of Surrey, Guildford, Surrey GU2 5XH, United Kingdom
Received July 2, 1996
ogy was always the same, namely, peptic ulceration before
combat, hepatic necrosis and often renal necrosis after
wounding, and occasionally, but much later, respiratory distress. Hardly ever did one see the wound infections that were
endemic in earlier wars, doubtless because of the liberal use
Although the study of poisons was an aspect of many
of sulfanilamide in wound dressing, and the subsequent use
ancient cultures, including the Egyptians (snake venoms,
of penicillin. The life-saving benefits of intravenous 5% glucardiac glycosides) (Oehme et al., 1980), the Chinese (opium
cose-saline had been learned in World War I, but saline
alkaloids) (Terry and Pellens, 1928), the Incas (coca and
perfusion was generally applied only after the wounded pastrychnos alkaloids), and the Greeks (hemlock) (Kingsbury,
tient had left surgery, mainly because the saline containers
1980), their knowledge of toxicology was descriptive and
were glass bottles that had to be suspended, thus presenting
empirical. Toxicology as we know it today—with its underdifficulties under field conditions. However, experience soon
standing of chemical mechanisms, detoxication, the biologishowed that early intravenous perfusion with glucose-saline
cal-chemical warfare of coevolution, and the concept of
was the critical determinant of speedy recovery. Apart from
selective toxicity in the design of medicines, pesticides, and
the arrest of hemorrhage, immediate surgical treatment was
food additives (Albert, 1985)—is a fundamental new sciless important in determining progress, and transfusion with
ence that is revolutionizing medicine and greatly improving
whole blood was seldom necessary.
society by its multifaceted impacts.
Early 1945 was spent in the Pacific on a British hospital
Battle trauma. My own debut with toxicology came in ship, supporting the internecine landings on Iwo Jima and
the early 1940s when, as a medical student, I became per- Okinawa, as we neared our goal of the Japanese mainland.
plexed with two major problems, namely, (1) why exposure In between battles there were opportunities for recuperation
to benzene caused chemical workers to develop scorbutic and research, and our earlier findings that the principal cause
symptoms, aplastic anaemia, and finally malignancy, and (2) of death of postsurgical battle casualties was hepatic failure
why war casualties died not of any subsequent infection, but were amply confirmed. This provoked general disbelief
of liver and kidney failure. Fifty years later these problems among the medical staff of the Allied forces, as the major
have only partly been resolved, but their study has revealed anaesthetics in use at that time were diethyl ether, nitrous
a common mechanism of toxicity which now appears to be oxide, trichloroethylene, and pentothal, which were considbasic to many toxic processes, namely, the generation of ered to be nontoxic (Bourne, 1936). Chloroform, which was
"oxygen radicals," or, to be more precise, "reactive oxygen known to cause hepatotoxicity, was no longer in use. Several
species" (ROS) (Dormandy, 1989; Halliwell, 1993). Be- U.S. aircraft carriers, utilized as hospital ships in these amcause of the Second World War, the second of these prob- phibious landings, were centers for medical seminars and
lems became the more imperative, especially as it increased discussions and collaboration with our American colto result in major epidemics of peptic ulceration and respira- leagues—for they had better equipment, and we had greater
tory distress among servicemen, which have since been re- stocks of penicillin. This gave us access to their comprehenlated to battle trauma and ROS toxicity. In Europe, North sive medical texts and journals, and it was while perusing
Africa, and the war zones of the Pacific, the pattern of pathol- these ships' libraries that I stumbled across some of the
origins of modern toxicology, going back to some of the
1
Dr. Dennis V. Parke was declared an Honorary Member of the Society
medical problems of the previous world conflict.
The Phoenix of Modern Toxicology. PARKE, D. V. (1996). Fundam. Appl. Toxicol. 34, 1-4. C 1996Sode«yof Toxkotogy.
of Toxicology at the 35th Annual Meeting of the Society, held in Anaheim,
California, in March, 1996. Portions of this article were contained in an
address given by Dr. Parke at the awards ceremony.
Gallipoli and discovery of glutathione. The battle of
Gallipoli in World War I was a military fiasco, generally
1
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Copyright C 19% by the Society of Toxicology
All rights of reproduction in any form reserved.
COMMENTARY
considered to be an ill-conceived whim of Winston
Churchill, the Minister for War at that time. Thousands of
British, Anzac (Australia and New Zealand), and Indian
troops had been slaughtered by the Turkish guns as the Allies
valiantly tried to establish a beachhead on the Crimean peninsula, and to scale the wire-covered slopes to reach the
Turkish positions. Often men were trapped on the wire for
several days, until they finally died from their wounds and
"battle shock." Although the United States was not officially involved in the war at that time, a number of American
surgeons and volunteers from the Quaker, and other, organizations left Philadelphia for Gallipoli, where they did sterling
work in rescuing the wounded and giving much-needed medical care. One important early finding of the Philadelphian
surgeons was that, of the wounded who had often spent days
"on the wire," diose receiving glucose-saline by parenteral
infusion for 24 h before going to surgery experienced much
lower rates of mortality than those rushed immediately to
surgery (Babcock, 1944). Administration of fluids, glucose,
and other nourishment by mouth had a similar beneficial
effect on postsurgical mortality rates. These American surgeons, like ourselves 30 years later, also found hepatic necrosis in those soldiers who died from their wounds, and came
to the conclusion that liver damage was the probable cause
of death. They further concluded that there was a natural
substance in liver, essential for hepatocyte integrity, that was
depleted by blood loss, trauma, or anaesthesia, but could be
replenished rapidly by intravenous glucose—saline, and less
readily by oral feeding (Babcock, 1944). This historical account of battle surgery was found in several American textbooks of surgery published from 1922 onward, but none was
discovered in any British text.
In the hope of elucidating the nature of this cytoprotective
material that occurred in liver, the American surgeons sought
collaboration from their chemist colleagues in the United
States and Europe. Sherwin and Stekol approached the problem using die hepatotoxic chemical bromobenzene as a
model system, while the British biochemist Hopkins sought
to isolate the cytoprotective material from liver tissue. Earlier workers had shown that bromobenzene was metabolized
by dogs to the jV-acetylcysteine conjugate /?-bromophenylmercapturic acid (Williams, 1947), resulting in its detoxication. Sherwin was the first to consider diat the liver might
have a role in the detoxication of toxic chemicals (Sherwin,
1922), and constantly directed his research toward such aspects of toxicology (Di Carlo et al, 1992). Hopkins (1921)
isolated an autoxidizable sulfur compound from liver which
he eventually identified as a tripeptide of cysteine, glutamic
acid, and glycine, and considered this to be a ubiquitous
intracellular redox buffer. Later, Stekol (1937) showed that
glutathione, and odier sulfur-containing compounds, decreased the toxicity of p-bromobenzyl bromide and increased
mercapturic acid formation, but it was not until much later
(Boyland et al, 1957; Knight and Young, 1957) that the
role of glutathione in detoxication and mercapturate biosynthesis was established unequivocally. Hence, the clinical observations of American surgeons in 1915 stimulated investigations which led eventually to the discovery of glutathione
and its role in protecting against the toxicity of chemicals
and surgical trauma—one of the major tenets of modern
toxicology.
Nuclear holocaust. In the autumn days of 1945, amidst
rumors of Japanese surrender, we steamed with the Combined Fleet into Tokyo Bay and then by train to Hiroshima
and Nagasaki. The effects of the nuclear bombing of the
Fatter two cities were catastrophic, but scarcely distinguishable from those of the genocidal fire-bombing of Tokyo.
Casualties with third-degree burns from ionizing radiation
differed little from those sustained from incendiarism, and
our primitive treatment at the time was essentially the same
for both—hypertonic saline gauze. The destructive biological effects of ionizing radiation, and of the oxygen radicals
(ROS) so produced, were well understood by scientists at
that time, but little was known concerning appropriate treatment or prophylaxis, or of the systemic toxicological effects.
Medical expertise was scant and essentially theoretical; staff
of the Curie's laboratory in London, where I had received
superficial training in radiation medicine as a student in the
early days of the war, had lost fingers and bore other scars,
and leukemias were known to be associated with exposure
to radioisotopic materials.
To repair this gap in medical knowledge, and obviously
to protect our armed forces and civilian populations against
possible future exposures to radioactive materials, a large,
long-term study of the toxic effects of ionizing radiation on
dogs was planned immediately after the war ended. This was
set up on the Davis campus of the University of California; I
was privileged to be taken in a USAF B29 from Tokyo to
Bakersfield, California, to be involved in the design and
planning of the study, and then to return to examine progress
some 30 years later in 1978. Potential protection and prophylaxis aspects were built into the multigeneration study, and
one early finding was that butterfat was protective against
radiation injury. Butterfat, taken enterally and applied topically, had long been known as a traditional Irish remedy for
severe burns, but had been ridiculed by the professionals.
In the light of more recent knowledge, this finding might
have been predicted, since (1) the protective effects of intracellular glutathione, ascorbate, and tocopherol against ROS
and oxidative stress may be augmented by NADPH (Parke
et al, 1996), and butyrate is one of the most rapidly metabolizable sources of energy and NADPH generation; (2) malignancy is dependent on increased rates of mitosis, and butyrate inhibits mitosis and cell division (Lupton, 1995; Hill,
1995); and (3) dietary butter fat has been shown to inhibit
malignancy (Yanagi et al, 1992).
COMMENTARY
Oxygen radical toxicity. Although much was known
about the chemistry of oxygen radicals (ROS) in the 1930s,
little was known of their biochemical effects or their roles
in toxicological processes. The advent of nuclear weaponry
and nuclear power generation brought renewed interest in
ROS toxicity and their role in pathological processes. In the
early postwar years it was realized that glutathione has two
major roles in protection against toxicity, namely, (1) as
Hopkin's intracellular redox buffer, protecting the cell
against ROS toxicity, oxidative stress, lipid peroxidation,
and cell death, and (2) as the coenzyme for glutathione conjugations, the biosynthesis of mercapturic acids, and the detoxication of toxic chemicals (Piotrowski and Parke, 1996).
At the same time, in the ensuing explosion of interest in
toxicology, it was appreciated that the toxic chemical benzene was radiomimetic, so its metabolism and toxicology
were studied in the hope of further elucidating the mechanisms of toxicity of ionizing radiation, ROS, and radiomimetic chemicals, and also of providing fundamental data
concerning the mechanisms of toxicity of the increasing
array of aromatic chemicals (Parke, 1996).
Because of the obvious protective effect of glutathione
against battle injury, it was also considered that ROS, or
the anesthetics in use at that time, might cause glutathione
depletion resulting in oxidative stress and hepatic and renal
failure. Early attempts in the 1950s to show an association
between exposure to ROS (X radiation), toxic chemicals
(benzene, bromobenzene), glutathione depletion (fasting),
and hepatic injury were unsuccessful, although other workers
later showed a dependence of acetaminophen (paracetamolinduced hepatotoxicity on fasting (Pessayre et ai, 1979), a
highly important finding. Studies on the metabolism of benzene confirmed the formation of catechol, quinol, and hydroxyquinol, all of which produce quinones and generate
ROS by redox cycling; cis-cis-muconic acid, formed via
muconaldehyde, may also generate ROS, and a minor metabolite, L-phenylmercapturic acid, provides evidence of conjugation with glutathione, all indicating that the radiomimetic
properties of benzene could be attributed to ROS generation
and glutathione depletion (Parke, 1996).
The studies on the mechanism of battle injury were made
more apposite by the appearance of a new toxic phenomenon, a new clinical syndrome, known as multiple system
organ failure (MSOF) (Fly, 1992). Today, the high incidence
of road traffic accidents replaces casualties from battle injury, and the emergence of antibiotic-resistant strains of microorganisms has brought a return of wound infections, both
of these contributing to inflammatory disease, ROS toxicity,
liver failure, and MSOF (Fly, 1992). In collaboration initially
with the Trauma Centre, Beijing, it was decided to return to
the conditions pertaining at Gallipoli in 1915, and to study
the effects of these on experimental animals, both singly and
collectively (Liu etal, 1991). Conditions studied were blood
loss, fasting, dehydration, glucose-saline perfusion, ether
anesthesia, ischemia, and reperfusion (Jaeschke et ai, 1988).
The overall outcome was that fasting and ether anesthesia,
singly and additively, induce cytochrome P450 2E, resulting
in high levels of ROS production (Ekstrom and IngelmannSundberg, 1989); fasting also leads to impaired NADPH
formation and decreased glutathione regeneration (Liu et ai,
1991, 1993a). Similarly, hemorrhage, hepatic ischemia, and
liver reperfusion in rats, as a model for blood loss and subsequent intravenous perfusion, were shown to result in lipid
peroxidation, loss of tissue GSH, and oxidative stress, more
associated with the period of intravenous reperfusion and
tissue infiltration by polymorphonuclear leucocytes than
with the ischemia (Liu et al, 1994). The proposed mechanism for this new toxicological phenomenon of MSOF involves chemical toxicity, induction of cytochrome P450 2E,
generation of ROS, depletion of intracellular GSH and other
antioxidants, oxidative stress (McCord, 1985), destruction
of other cytochromes P450, lipid peroxidation, leukotriene
production, interleukin activation, leukocyte activation, and
leukocyte infiltration of tissues, in a progressive pattern of
inflammation (Parke and Parke, 1995; Wiseman and Halliwell, 1996), tissue necrosis, and organ failure (Liu et al,
1993b, c, d, 1994).
Renaissance. The role of ROS in the causation of battle
trauma and chemical-induced MSOF (Liu et al., 1994), in
the toxic effects of ionizing radiation, and in the ultimate
pathology of the radiomimetic toxicity of benzene (Parke,
1996) indicates a common molecular mechanism, which recently has been shown to be much more widespread, embracing many chemicals, and fundamental to most mechanisms
of toxicity (Sapota and Parke, 1996), including carcinogenicity (Wiseman and Halliwell, 1996; Parke, 1994; Parke etal.,
1996). The years following World War II, and the discovery
of antibiotics and other drugs, have seen a progressive expansion of the pharmaceutical industry, a public realization of
the problems of chemical toxicity and environmental pollution, and the setting-up of government agencies, such as the
FDA, NIH, NCI, EPA, and OSHA, to regulate food and
drug safety, and to study problems of chemical toxicity,
industrial pollution, and environmental health.
So toxicology was born, and from the ashes of Pearl Harbor, Hiroshima, and Tokyo, and from the rubble of London,
Berlin, and Dresden, arose the phoenix of modem toxicology, bringing with it new hopes for the health of mankind,
with antibiotics, anticancer treatments, anti-inflammatory
and cardiovascular drugs, with cleaner environments, safer
food and drink, and new developments in occupational medicine and environmental health.
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