PHAR 303 Lecture Notes - Lecture 9: Edwin Smith Papyrus, Aspergillus Flavus, Chimney Sweep
11 May 2018
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Lecture 9 (Feb 6) Carcinogens & their targets
Cancer
• Normal cells are damaged – often DNA damage
• Abnormal growth of cells
• Dysregulation in the balance between cell proliferation and cell death – too much cell proliferation vs
cell death
• Multiple changes in gene expression
• When you look at all causes of death in Canada, cancer is the biggest (30.2%)
• Over 200k Canadians diagnosed with cancer in 2017
• 80k will die of cancer in 2017
• ½ Canadians develop cancer in their lifetime
• 800k Canadians were alive at the beginning of 2009 with cancer diagnosed in previous 10 years
Causes of cancer
• Free radicals, general air pollution, toxic waste, benzoapyrene, EtBr, Arsenic
• Tobacco (highest cause – 25-40% of all human cancers), adult diet/obesity, sedentary lifestyle,
occupational factors, genetics, viruses, perinatal factors, reproductive factors, socioeconomic status,
alcohol, drugs/medication, environmental pollution, ionizing/UV radiation, salt/food
additives/contaminants.
• 70-90% of cancers have a link to environmental & lifestyle factors.
Carcinogen
• Agent that significally increases incidence of neoplasms (cancer lesion)
• Any substance (including radionuclide & radiation) that’s directly involved in causing cancer.
• Can also be a natural substance – Aflatoxin B (from certain molds)
• There are approx. ~200 known chemical csrcinogens
• Damage the genome or disrupt cellular metabolic processes.
• To be a carcinogen the substance may require a metabolic activation (toxication)
Human exposure to Chimney sweeper Benzoapyrene Scrotal Cancer
Aspergillus flavus (growing on corn) Aflatoxin B Liver Cancer
Tobacco Benzene, Formaldehyde, Acetaldehyde, Butadiene Lung & other cancers
History of Cancer – Ancient disease, described thousands years ago
Edwin Smith Papyrus
• Antiquities dealer who bought the papyrus in 1862
• Ancient Egyptian medical text
• Oldest known surgical document (3000BC , 48 cases of wounds, injuries, fractures)
• Oldest description of cancer (but the word cancer was not used)
• Describes 8 cases of tumors – no treatment
Hippocrates (460-370 BC)
• Father of modern medicine
• Believed disease were caused naturally – not because of punishment inflicted by gods
o Product of environmental factors, diet, living habits
• Described several kinds of cancer – breast cancer as a humoral disease (imbalance of the humors/ body
fluids, black bile)
• First to give a name to it “Karkinos (carcinos)/ carcinoma (carcinoma)”
o Greek word for crab crayfish due to the appearance of the solid malignant tumor as its “veins
stretched out like a crab has its feet”
Percivall Pott (1714-1788)
• English surgeon – first to associate that a cancer could be caused by an environmental carcinogen
• 1755: Soot causes scrotal cancer in chimney sweeps – little boys were sent to clean up the chimneys,
wearing very little protection or clothes.. By the time they would get down, they were covered in soot,
aches of chimneys.
o By the time of puberty, onset of cancer
o Originally termed “Pott’s cancer” “Chimney sweepers’ cancer”
find more resources at oneclass.com
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• First description on an occupational cancer – observations linked this type of cancer to environment
exposures
• Act of Parliament (1840) – no chimney sweep under the age of 21
Yamagiwa & Ichikawa (1915) – experimental evidence of environmental causes of cancer
• First to show that a chemical could produce cancer
• Application of coal tar on rabbit ears produced skin cancer (malignant epithelial tumors)
o 250 days of painting/ application crude coal tar on inner surface of rabbits ears
o Had no idea what substance in the coal was causing the cancer
But it was the British who identified the carcinogenic components from the mixtures
• Cook, Hewett & Hieger 1933
• Identification of PAH: Polycyclic aromatic hydrocarbons , benzo[a]pyrene as the active component of
coal tar
• Used 2 tons of coal tar pitch (thick, black liquid after distillation of coal tar)
• Pitch is used as base coating of paint, roofing, paving
Experimental production of carcinoma with cigarette tar (Wynder, 1953)
• Cigarette smoke as a chemical mixture –leading cause of death & lung cancer
• Initially, lung cancer was thought to be caused by cigarette dust & not the smoke itself
• It wasn’t until 1953,that there was experimental evidence that the smoke was the cause
• Tabacco tars collected from cigarettes & dissolved in acetone
• Designed a smoking apparatus – smoke 60 cigarettes at a time for a total of 50 cartons of cigarettes –
then collected the smoke in the condensing flasks & dryed & dissolved
• Cigarette tar was applied to dorsal area of mice – led to development of cancer
Classification of Carcinogens
IARC - International Agency for Research on Cancer – specialized cancer agency of the World Health
Organization (WHO) that was created on May 20, 1965 (France)
• Objective is to promote international collaboration in cancer research
• Identify causes of cancer so preventative measures can be adopted
• Elucidate the role of environmental lifestyle risk factors by doing studies
o Population-based studies (human)
o Experimental models (animals)
• Published a series of IARC Monographs – series of scientific reviews that identify the environmental
factors that increase cancer risk & Classify carcinogens
• 4 groups/classes of carcinogens based on experimental evidence
o Group 1 (+1) – Carcinogenic to humans (120) – human and animal data strong
Carcinogenic to humans because sufficient evidence of carcinogenicity in humans OR when evidence in
humans is less than sufficient but there is sufficient evidence in experimental animals and strong
evidence that the agent acts through a relevant mechanism of carcinogenicity
▪ Asbestos, soot, diesel exhaust
o Group 2A – Probably carcinogenic to humans (81) – human data suggestive but limited & Positive
Animal Data (DDT - pesticide)
o Group 2B – Possibly carcinogenic to humans (299) – human data weak & animal data positive/limited
(Chloroform)
o Group 3 – Not classifiable as to its carcinogenicity to humans (502) – Human & animal data
inadequate/limited (Caffeine)
o Group 4 – Probably not carcinogenic to humans (1) – Human & Animal data negative (Caprolactam –
organic compound used to make synthetic fibres)
Ex. Your supper according to the IARC
Coffee, chlorinated water – group 3
High temperature frying (acrylamide) & Red meat group 2A if charbroiled (7oz) contains 10 ug B[a]p –
group 1
Alcoholic beverages – group 1
Carcinogens can be classified based on:
• Physical properties– radiation
• Biological – viruses (HPV, EBV, HBV)
• Chemical – genotoxic or non-genotoxic
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Lecture 9 (feb 6) carcinogens & their targets. Carcinogen: agent that significally increases incidence of neoplasms (cancer lesion, any substance (including radionuclide & radiation) that"s directly involved in causing cancer, can also be a natural substance aflatoxin b (from certain molds, there are approx. ~200 known chemical csrcinogens: damage the genome or disrupt cellular metabolic processes, to be a carcinogen the substance may require a metabolic activation (toxication) Human exposure to chimney sweeper (cid:314) benzoapyrene (cid:314) scrotal cancer. Aspergillus flavus (growing on corn) (cid:314) aflatoxin b (cid:314) liver cancer. Tobacco (cid:314) benzene, formaldehyde, acetaldehyde, butadiene (cid:314) lung & other cancers. History of cancer ancient disease, described thousands years ago. But it was the british who identified the carcinogenic components from the mixtures: cook, hewett & hieger 1933. Initially, lung cancer was thought to be caused by cigarette dust & not the smoke itself. It wasn"t until 1953,that there was experimental evidence that the smoke was the cause.
