{"id":4177,"date":"2014-03-28T00:05:46","date_gmt":"2014-03-27T23:05:46","guid":{"rendered":"http:\/\/emilkirkegaard.dk\/en\/?p=4177"},"modified":"2014-10-09T18:20:50","modified_gmt":"2014-10-09T17:20:50","slug":"an-introduction-to-toxicology-burcham-philip-c","status":"publish","type":"post","link":"https:\/\/emilkirkegaard.dk\/en\/2014\/03\/an-introduction-to-toxicology-burcham-philip-c\/","title":{"rendered":"An Introduction to Toxicology (Burcham, Philip C.)"},"content":{"rendered":"

https:\/\/www.goodreads.com\/book\/show\/19824663-an-introduction-to-toxicology<\/a><\/p>\n

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http:\/\/gen.lib.rus.ec\/book\/index.php?md5=3b495b4fd548e7574a0ec998f22afac6&open=0<\/a><\/p>\n

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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 \u201ctoxicology\u201d 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.<\/p>\n

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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.<\/p>\n

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–<\/p>\n

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For reasons that are not entirely clear, two disreputable businessmen in Boston, <\/span><\/p>\n

Harry Gross and Max Reisman, hit upon the idea of adulterating their Ginger Jake <\/span><\/p>\n

product with the plasticiser tri-O-cresyl phosphate (TOCP ), then manufactured by <\/span><\/p>\n

the Eastman Kodak company for use in lacquers and varnishes. Unaware of its toxic <\/span><\/p>\n

properties, Gross and Reisman purchased 135 gal of TOCP and added it to Ginger <\/span><\/p>\n

Jake batches that were used to fill hundreds of thousands of bottles. The product was <\/span><\/p>\n

then sold throughout the continental USA. The resulting delayed-onset neurotoxic <\/span><\/p>\n

syndrome seen in users of the product was nicknamed \u2018Jake Walk\u2019 due to the paralysing loss of leg muscle tone that progressed to the point where victim\u2019s feet <\/span><\/p>\n

flopped like those of a marionette (Fig. 1.5). Nationwide, around 40,000\u201350, 000 <\/span><\/p>\n

people were affected in a disaster that unfolded rapidly: in Wichita, Kansas, around <\/span><\/p>\n

500 patients manifested signs of TOCP intoxication in a single night alone. Although <\/span><\/p>\n

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 <\/span><\/p>\n

dozen references to \u2018Jake Walk\u2019 in commercial phonograph recordings by jazz <\/span><\/p>\n

musicians of the time.<\/span><\/p>\n

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Neat illustration of a black market effect on alcohol.<\/p>\n

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https:\/\/en.wikipedia.org\/wiki\/TOCP<\/a><\/p>\n

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–<\/p>\n

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In addition to synthetic substances, the term xenobioticcovers naturally occurring <\/span><\/p>\n

chemicals to which humans are regularly exposed via consumption of plant- based <\/span><\/p>\n

foodstuffs, botanical beverages and herbal remedies. While many of these substances <\/span><\/p>\n

are likely harmless or even beneficial to human health, some xenobiotics of natural <\/span><\/p>\n

origin can be very harmful indeed. As a rule, modern toxicology does not concur <\/span><\/p>\n

with the popular belief that foreign or synthetic chemicals are inherently more toxic <\/span><\/p>\n

than naturally occurring substances or even endobiotics. Many of the most toxic <\/span><\/p>\n

substances known to toxicology are of natural origin \u2013 a point that will be reinforced <\/span><\/p>\n

throughout this book. Nevertheless, synthetic chemicals of human origin typically <\/span><\/p>\n

attract the greatest attention in modern toxicology simply because they are used on a <\/span><\/p>\n

vast scale in today\u2019s industrial societies. So while nature may produce some highly <\/span><\/p>\n

potent toxins, they are rarely produced on a comparable scale to modern synthetic <\/span><\/p>\n

substances. Another factor that maximises interest in synthetic xenobiotics is their <\/span><\/p>\n

frequent possession of physicochemical features that ensure they are long lived <\/span><\/p>\n

within biological systems or the wider environment. Since we have been exposed to <\/span><\/p>\n

natural chemicals throughout human history, our bodies are better adapted to coping <\/span><\/p>\n

with their presence compared to some synthetic substances of modern origin that <\/span><\/p>\n

may contain unusual chemical properties that render them resistant to metabolism. <\/span><\/p>\n

 <\/p>\n

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 <\/span><\/p>\n

sensitive analytical instruments for the detection and quantitation of chemicals in <\/span><\/p>\n

body fluids or tissues, we now know that many chemicals \u2013 even some we once <\/span><\/p>\n

assumed were entirely of synthetic origin and would only be encountered in the factory or industrial workplace \u2013 are actually formed at low levels within the body. <\/span><\/p>\n

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 <\/span><\/p>\n

tobacco, fossil fuels and forest vegetation. Acrolein also forms during cooking <\/span><\/p>\n

processes and can attain high airborne concentrations in kitchens if deep fried foods <\/span><\/p>\n

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 <\/span><\/p>\n

by the discovery that it forms endogenously via diverse biochemical processes, <\/span><\/p>\n

including a phenomenon termed lipid peroxidationwhich we will examine in <\/span><\/p>\n

Chap. 4 (Sect. 4.4.4). Some scientists suspect that endogenous acrolein participates <\/span><\/p>\n

in such degenerative diseases of old age as Alzheimer\u2019s dementia. This remains to <\/span><\/p>\n

be fully proven, and ongoing research is assessing the health significance of these <\/span><\/p>\n

endogenous exposures. It could well be that for some endogenous exposures, the <\/span><\/p>\n

high sensitivity of our modern analytical instruments leads us to overestimate their <\/span><\/p>\n

importance. Nevertheless, the fact that we are exposed to noxious substances from <\/span><\/p>\n

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)?<\/span><\/p>\n

 <\/p>\n

A handy reference for appeal to nature fallacy.<\/p>\n

 <\/p>\n

–<\/p>\n

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Idiosyncratic sensitivity sometimes occurs because individuals express mutated <\/span><\/p>\n

or polymorphic versions of enzymes that cannot properly metabolise toxicants to <\/span><\/p>\n

facilitate their bodily elimination. In some ethnic populations, mutant xenobiotic- <\/span><\/p>\n

metabolising genes are so prevalent that they influence prescribing decisions by <\/span><\/p>\n

physicians. A famous example of this phenomenon involves the tuberculosis drug <\/span><\/p>\n

isoniazid, which causes liver damage in ~1 % of patients. The conjugative enzyme <\/span><\/p>\n

N-acetyl transferase 2 (NAT2) plays an important role in isoniazid metabolism, and <\/span><\/p>\n

studies in a variety of ethnic groups have associated a genetic deficiency in NAT2 <\/span><\/p>\n

(known as \u2018slow acetylators\u2019 due to their reduced ability to metabolise isoniazid and <\/span><\/p>\n

other xenobiotics) with an increased susceptibility to liver injury.<\/span><\/p>\n

 <\/p>\n

–<\/span><\/p>\n

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Historically, much attention has been directed to CYP2D6 polymorphisms, due <\/span><\/p>\n

to the early discovery of patient subgroups that display exaggerated responses to the <\/span><\/p>\n

cardiovascular drugs debrisoquine and sparteine. The inability to metabolise <\/span><\/p>\n

debrisoquine was linked to a 2D6 polymorphism that was found to vary in its prevalence in different ethnic groups (e.g. 5\u201310 % of Caucasians are \u2018poor metabolisers <\/span><\/p>\n

(PM)\u2019, while the incidence in Asian populations is ~ 1 %). Using such techniques as <\/span><\/p>\n

restriction fragment length polymorphism, PCR and gene sequencing, over 110 <\/span><\/p>\n

polymorphisms were subsequently identified in the CYP2D6 gene. Genetic variants <\/span><\/p>\n

that exist at the same chromosomal locus are termed alleles. Although the number <\/span><\/p>\n

of 2D6 alleles is unusually large, allele numbers are typically high for most xenobiotic biotransformation genes compared to other genetic loci.<\/span><\/p>\n

 <\/p>\n

The importance of genomic sequencing and attention to racial groups as these provide a proxy for these values.<\/p>\n

 <\/p>\n

 <\/p>\n

 <\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

https:\/\/www.goodreads.com\/book\/show\/19824663-an-introduction-to-toxicology   http:\/\/gen.lib.rus.ec\/book\/index.php?md5=3b495b4fd548e7574a0ec998f22afac6&open=0   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, […]<\/p>\n","protected":false},"author":17,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1107],"tags":[1067,1701,1999],"class_list":["post-4177","post","type-post","status-publish","format-standard","hentry","category-science","tag-review","tag-textbook","tag-toxicology","entry"],"_links":{"self":[{"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/posts\/4177","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/users\/17"}],"replies":[{"embeddable":true,"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/comments?post=4177"}],"version-history":[{"count":2,"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/posts\/4177\/revisions"}],"predecessor-version":[{"id":4345,"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/posts\/4177\/revisions\/4345"}],"wp:attachment":[{"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/media?parent=4177"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/categories?post=4177"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/emilkirkegaard.dk\/en\/wp-json\/wp\/v2\/tags?post=4177"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}