Smoking, alcoholism,drug induced diseases, obesity

Dr. Attila Zalatnai

(For educational purposes only)

A.R.C. (International Agency for Research on Cancer) has an interesting history. It was established at

the suggestion of Charles de Gaulle, first President of France after the Second World War. He

suggested that it might be a good idea for the industrialised countries of the world to contribute

approximately 1% of their military budget each year for research on cancer. This idea was accepted

by W.H.O. The Mayor of Lyon offered that the city would build a research institution with an

appropriate lecture/conference hall on land in the centre of the hospital and university area in Lyon.

The city would lease the building and land to W.H.O. for 1 French franc per year.

The mailing centre for the tumour books in the IARC headquarters in Lyon. The Chief Librarian, Sue Cotterell,

is in the foreground.

Thus, the I.A.R.C. started its work in July 1965. The original buildings are still in use. A new lecture

theatre was built in 1988 with money donated by the Japan Shipbuilding Industry Foundation of

which Mr Ryoichi Sasakawa was Chairman. Another series of buildings was added with further

money provided by the governing council of I.A.R.C., together with money provided by donations

from other outside organisations. I.A.R.C.’s mission is stated as being cancer research for cancer

control with four main arms -

• Monitoring global cancer occurrence

• Identifying the causes of cancer

• Elucidation of mechanisms of carcinogenesis

• Developing scientific strategies for cancer control

The IARC categorizes agents, mixtures

and exposures into five categories.

•Category 1:

carcinogenic to

humans.

• Category 2A:

probably carcinogenic

to humans.

• Category 2B:

possibly carcinogenic

to humans.

• Category 3: not

classifiable as to

carcinogenicity in

humans.

•Category 4:

probably not

carcinogenic to

humans.

Cigarette smoke:

Category 1 (carcinogenic to

humans)

Component Harmful effect

Tar

Polyclic aromatic hydrocarbons (PAH)

Benz(a)pyrene

Dimethyl-benzanthracene

Benzo(b,j)fluorantrene

5-methylchrysene

3-methylcholantrene

NNK (nicotine-derived nitrosamine keton)

Nitrosamines (DEN, DMN)

Aromatic amines

Metals (chromium, cadmium, nickel

subsulfid, arsenic)

Polonium-210

Lactones

Fenols, fenol derivates

Formaldehid, acetaldehide

Benzene

Acrolein

Carbon monoxide

carcinogenic

carcinogenic

strong carcinogenic (paper!!)

strong carcinogenic

moderate carcinogenic

carcinogenic

promoter

lung-specific carcinogen (+ pancreas)

carcinogens

urinary carcinogens

carcinogens

radioactive compound (-emission)

strong carcinogens

promoters

mucosal irritants

Leukemogenic, myelodepressive

microvillus immobilizer

carboxyhemoglobin-production

Some very harmful compounds of the cigarette smoke

1. Carcinogenic effects

2. Vascular effects

(atherosclerosis, Buerger’s

disease

3. Respiratory effects (COPD)

4. Gastrointestinal effects

5. Effect on pregnancy (fetal

hypoxia, spontatneous

abortions, small-for date

babiesPancreas

Ethylalcohol

acetaldehyde

Critical amount inducing liver

damage:

Men: 80 g pure alcohol/day

Women: 20 g /day

Beer (4 %) = 2 liters/0.5 liters

Wine (8 %) = 1 liter/2,5 dl

Palinka (40 %) = 2 dl/0.5 dl

Target organs:

• liver

• pancreas (chronic fibrotizing pancreatitis)

• heart (alcoholic cardiomyopathy)

• stomach (mucosal atrophy, ulcer)

• CNS (cortical atrophy)

• fetus (fetal alcohol syndrome)

fatty change

alcoholic hepatitis

micronodular liver

cirrhosis

Decompensation

Parenchymal Vascular

icterus portal hypertension

hepatic encephalopathy splenomegaly

hepatorenal syndrome caput Medusae

esophageal varices

ascites

Other complications

spontaneous bacterial peritonitis

bleeding tendency

gynecomastia

spider nevi

risk for HCC!

Obesity

(not just a cosmetical/esthetic

problem!)

Increased risk for……

Hyperlipidemia

Atherosclerosis

Diabetes mellitus

Arthrosis

Chronic cor pulmonale

Varicosity

Endometrial cancer

Drug-induced pathological conditions

The Contergan-story

(thalidomide)

TUMOR THERAPY

Myelodepression, thrombopenia

Cyclophosphamide: hemorrhagic urocystitis

Bleomycin – pulmonary fibrosis

Adriamycin – myocardial damage

Induced, secondary tumors

Cytostatics : „carcinogens to humans", or„probably carcinogens to humans” (IARC)

TARGETED THERAPIES

Generally: good toxicologic profile

BUT: unpredictable, sometimes fatal side effects

cetuximab

(EGFR Mab)

gefitinib – 2 % interstitial lung disease (0,8 % fatal)

Herceptin – congestive cardiomyopathy

antiangiogenetics– gastrointestinal perforations

IMMUNOLOGICAL TOXIKOLOGICAL

- Usually more than one dosis is necessasry - Frequently one dose is enough

- Not always dose-deoendent - Severity of side effects is dose-dependent

- Withdrawal (in most cases) leads to

quick recovery

- The total amount of the drug is an

important factor

- Reactions are variable, no organ specificity - Characteristic organ specificity

DRUG-INDUCED REACTIONS

Proton pump inhibitors (PPIs)