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Environmental Health: sanitation, water, pesticide and industrial residues 1. Describe methods of exposure to environmental chemicals Exposure to environmental chemicals can occur via: skin contact inhalation ingestion (food, water) eye contact vertical transmission (mother to child in breast milk, placental transmission) 2. Discuss, using examples, the potential for the environmental agents to impact upon the cell cycle Carcinogenesis two steps → initiation and promotion First Stage: Initiation→ irreversible and rapid process whereby a chemical produces an irreversible change in the DNA of a target cell Second stage: Promotion → involves a series of reversible tissue and cellular changes during the long latency period before the appearance of the first autonomous cancer cell Progression → stepwise evolution of cancer cells as they become progressively more malignant (growing rapidly and unable to repair defects) Initiation of Carcinogenesis Carcinogens fall into one of two categories: 1. Direct acting carcinogens: do not require chemical transformation for their carcinogenicity. 2. Indirect acting carcinogens/procarcinogens: require metabolic conversion in vivo to produce ultimate carcinogens capable of transforming cells. Molecular targets of chemical carcinogens Malignant transformation results usually from mutations that affect oncogenes, tumour suppressor genes and genes that regulate apoptosis DNA is a primary target for chemical carcinogens, but there is no single alteration that can be associated with initiation of chemical carcinogenesis. Each class of carcinogens tends to produce a limited pattern of DNA damage. Thus, the presence of certain types of DNA damage in human tumours can provide molecular cues to their causation. Although any gene could be targeted, the ras and p53 genes are commonly involved p53 is a tumour suppressor gene that arrests cells in the G1/S phase of the cell cycle if there is DNA damage and induces apoptosis is the damage is too severe to be repaired ras is an oncogene (see Nic’s notes) malignant cells posses the ability to bypass the restriction on entrance into S phase normally imposed by damaged DNA this allows the cell to accumulate genetic changes and promotes the selective outgrowth of cells with a proliferative advantage most chemical carcinogens act by producing changes in DNA (initiation phase of carcinogenesis) Radiation direct effects on DNA or activation of oncogenes Aflatoxin (from fungus in improperly stored food) oxidized in the liver to a carcinogen that binds with guanine in DNA of hepatic cells Cigarette Smoking cigarette smoke contains numerous carcinogens most important is probably polycyclic hydrocarbons (tar) these are direct acting carcinogens on the skin, but are procarcinogens in lung and bladder cancer inhaled polycyclic hydrocarbons → converted in liver to an epoxide by a microsomal enzyme (aryl hydrocarbon hydroxylase) the epoxide (the ultimate carcinogen) combines with guanine in DNA leading to neoplastic transformation UV radiation causes linkages between pyrimidine bases on DNA 3. List examples of environmental carcinogens and mutagens Carcinogens are substances that are known to cause cancer or at least produce an increased incidence of cancer in a population. Mutagens are physical or chemical agents that change the genetic material of an organism and thus increase the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are typically also carcinogens. Chemical polycyclic hydrocarbons soot inhalation or chewing of tobacco products Aromatic Amines benzidine, 2naphthylamine Aflatoxins Nitrosamines Cancer therapeutic agents Alkylating agents (cyclophosphamide, chlorambucil, thiotepa, busulfan) Asbestos Source chimneys, air pollution skin; scrotal cancer in chimney sweeps mainly cigarettes lung, bladder, oral cavity, larynx, oesophagus first recognized in workers of the leather dye industries produced by the fungus Aspergillus flavus which grows on improperly stored food conversion of nitrities in the stomach (nitrites are ubiquitous in food because of their common use as preservatives) Vinyl Chloride bladder liver ? oesophagus, ? stomach leukaemias has been used as insulation material and fire retardant Alcohol Heavy Metals nickel, chromium, cadmium arsenic Types of Cancer lung, mesothelioma mouth, pharynx, larynx, oesophagus and liver miners lung agricultural workers exposed to arsenic containing pesticides skin gas used in PVC manufacture liver (angiosarcoma) Radiation Ultraviolet Source solar X-ray radiation therapy diagnostic Radioisoptopes Types of cancer skin (especially in fair people) malignant-neoplasms (often sarcomas) 10-15 years later dose believed to be too small to cause harm lung occupational exposure in mines radioactive iodine therapy increased cancer risk 15-25 (non-neoplastic thyroid years later disease) Nuclear Fallout Hiroshima, Nagasaki, several kinds of cancers Marshall Islands, Chernobyl *’man made’ radiation however accounts for less than 1% of total radiation exposure of the population. Most comes from the earth, rocks and cosmic radiation (i.e. unavoidable background radiation) Virus Hapatitis B Human papillomavirus Epstein-Barr virus Type of cancer liver cervix nasopharynx, Hodgkin’s bdisease, Burkitt’s Lymphoma