Friend of mine wants me to write a book chapter or two in his book advocating nuclear energy. Specifically, a chapter about toxicology and dose response models. I felt less than competent and so i decided to increase my toxicological knowledge with a textbook. I wanted an up to date one, so i searched libgen for “toxicology” and sorted by year of publication. Then i found this one. Googling it did not reveal any obvious evidence of low quality, so it seemed worth reading.
As it turned out, this book did not deal much with dose response models! It focused on mechanistic toxicology. For studying this my chemistry knowledge was not sufficient, so there was some content i did not fully understand.
For reasons that are not entirely clear, two disreputable businessmen in Boston,
Harry Gross and Max Reisman, hit upon the idea of adulterating their Ginger Jake
product with the plasticiser tri-O-cresyl phosphate (TOCP ), then manufactured by
the Eastman Kodak company for use in lacquers and varnishes. Unaware of its toxic
properties, Gross and Reisman purchased 135 gal of TOCP and added it to Ginger
Jake batches that were used to fill hundreds of thousands of bottles. The product was
then sold throughout the continental USA. The resulting delayed-onset neurotoxic
syndrome seen in users of the product was nicknamed ‘Jake Walk’ due to the paralysing loss of leg muscle tone that progressed to the point where victim’s feet
flopped like those of a marionette (Fig. 1.5). Nationwide, around 40,000–50, 000
people were affected in a disaster that unfolded rapidly: in Wichita, Kansas, around
500 patients manifested signs of TOCP intoxication in a single night alone. Although
partial recovery sometimes occurred, many victims were permanently incapacitated, spending the remainder of their lives in charitable institutions or county asylums. The epidemic also left its stamp on Southern popular culture, with at least a
dozen references to ‘Jake Walk’ in commercial phonograph recordings by jazz
musicians of the time.
Neat illustration of a black market effect on alcohol.
In addition to synthetic substances, the term xenobioticcovers naturally occurring
chemicals to which humans are regularly exposed via consumption of plant- based
foodstuffs, botanical beverages and herbal remedies. While many of these substances
are likely harmless or even beneficial to human health, some xenobiotics of natural
origin can be very harmful indeed. As a rule, modern toxicology does not concur
with the popular belief that foreign or synthetic chemicals are inherently more toxic
than naturally occurring substances or even endobiotics. Many of the most toxic
substances known to toxicology are of natural origin – a point that will be reinforced
throughout this book. Nevertheless, synthetic chemicals of human origin typically
attract the greatest attention in modern toxicology simply because they are used on a
vast scale in today’s industrial societies. So while nature may produce some highly
potent toxins, they are rarely produced on a comparable scale to modern synthetic
substances. Another factor that maximises interest in synthetic xenobiotics is their
frequent possession of physicochemical features that ensure they are long lived
within biological systems or the wider environment. Since we have been exposed to
natural chemicals throughout human history, our bodies are better adapted to coping
with their presence compared to some synthetic substances of modern origin that
may contain unusual chemical properties that render them resistant to metabolism.
Although it is handy to classify chemicals according to whether they are of natural or synthetic origin, this distinction is often artificial. With the development of
sensitive analytical instruments for the detection and quantitation of chemicals in
body fluids or tissues, we now know that many chemicals – even some we once
assumed were entirely of synthetic origin and would only be encountered in the factory or industrial workplace – are actually formed at low levels within the body.
Acrolein, for example, is a highly toxic carbonyl compound used during the manufacture of plastics and other synthetic chemicals (Fig. 2.1). It is also a major environmental pollutant, formed during the combustion of organic matter including
tobacco, fossil fuels and forest vegetation. Acrolein also forms during cooking
processes and can attain high airborne concentrations in kitchens if deep fried foods
are prepared over a poorly ventilated stovetop. Yet in recent decades, our assumption that acrolein is mainly ingested from these foreign sources has been overturned
by the discovery that it forms endogenously via diverse biochemical processes,
including a phenomenon termed lipid peroxidationwhich we will examine in
Chap. 4 (Sect. 4.4.4). Some scientists suspect that endogenous acrolein participates
in such degenerative diseases of old age as Alzheimer’s dementia. This remains to
be fully proven, and ongoing research is assessing the health significance of these
endogenous exposures. It could well be that for some endogenous exposures, the
high sensitivity of our modern analytical instruments leads us to overestimate their
importance. Nevertheless, the fact that we are exposed to noxious substances from
both external and internal sources poses a conceptual problem: should we categorise a substance like acrolein as a xenobiotic, an endobioticor both (Fig. 2.1)?
A handy reference for appeal to nature fallacy.
Idiosyncratic sensitivity sometimes occurs because individuals express mutated
or polymorphic versions of enzymes that cannot properly metabolise toxicants to
facilitate their bodily elimination. In some ethnic populations, mutant xenobiotic-
metabolising genes are so prevalent that they influence prescribing decisions by
physicians. A famous example of this phenomenon involves the tuberculosis drug
isoniazid, which causes liver damage in ~1 % of patients. The conjugative enzyme
N-acetyl transferase 2 (NAT2) plays an important role in isoniazid metabolism, and
studies in a variety of ethnic groups have associated a genetic deficiency in NAT2
(known as ‘slow acetylators’ due to their reduced ability to metabolise isoniazid and
other xenobiotics) with an increased susceptibility to liver injury.
Historically, much attention has been directed to CYP2D6 polymorphisms, due
to the early discovery of patient subgroups that display exaggerated responses to the
cardiovascular drugs debrisoquine and sparteine. The inability to metabolise
debrisoquine was linked to a 2D6 polymorphism that was found to vary in its prevalence in different ethnic groups (e.g. 5–10 % of Caucasians are ‘poor metabolisers
(PM)’, while the incidence in Asian populations is ~ 1 %). Using such techniques as
restriction fragment length polymorphism, PCR and gene sequencing, over 110
polymorphisms were subsequently identified in the CYP2D6 gene. Genetic variants
that exist at the same chromosomal locus are termed alleles. Although the number
of 2D6 alleles is unusually large, allele numbers are typically high for most xenobiotic biotransformation genes compared to other genetic loci.
The importance of genomic sequencing and attention to racial groups as these provide a proxy for these values.