1. 1. NON-ORGAN-DIRECTED TOXICITY
Molecular Mechanisms of Toxicology
1. NON-ORGAN-DIRECTED TOXICITY
2. TARGET ORGAN TOXICITY

2. Definitions
Neoplasia is often defined as the presence or formation of new, abnormal growth of tissue.
The resulting neoplastic lesion is referred to as a neoplasm.
Both benign and malignant neoplasms can be induced by chemical carcinogens.

3. Benign tissue is not cancer
Benign tissue is not cancer. Although the cell growth is moderately increased, the cells do not invade nearby tissue or spread to other parts of the body
Malignant tissue is cancer. The cancer cells divide out of control. They can invade and destroy nearby healthy tissue. Also, cancer cells can break away from the tumor they form and enter the bloodstream and lymphatic system
Metastasis: the spread of cancer beyond the organ of origin

4. Neoplasms
For benign neoplasms, the tissue of origin is frequently followed by the suffix “oma”; for example,
a benign fibrous neoplasm would be termed fibroma, and
a benign glandular epithelium termed an adenoma.
For Malignant neoplasms from
Epithelial origin are called carcinomas while
those derived from mesenchymal origin are referred to as sarcoma. Thus,
a malignant neoplasm of fibrous tissue would be a fibrosarcoma,
from bone would be an ostoesarcoma.
a malignant from the liver would be a hepatocellular carcinoma,
from skin would be referred to as a squamous cell carcinoma.

5. Tumor
A swelling of a part of the body, generally without inflammation, caused by an abnormal growth of tissue, whether benign or malignant. (Table 8-3).

7. MULTISTAGE CARCINOGENESIS
initiation
promotion
progression

8. Initiation
Tumor initiation is defined as "a process in which normal cells are changed so that they are able to form tumors". It is the first phase in tumor development. Mutagens, substances that cause cancer can be tumor initiators.
A process that is defined as a stable, heritable change.
This stage is a rapid, irreversible process that results in a carcinogen-induced mutational event.

9. Initiating agents
Chemical and physical agents that function at this stage are referred to as initiators or initiating agents.
Initiating agents lead to genetic changes including mutations and deletions.
initiating carcinogens are classified as
Chemical carcinogens that covalently bind to DNA and form adducts that result in mutations are initiating agents. chemicals polycyclic hydrocarbons and nitrosamines,
biological agents such as viruses, and
physical agents such as X-rays and UV light.

11. Promotion
The stage of promotion requires repeated applications of a second compound, called the promoter, which by itself is incapable of inducing carcinogenesis.
Reversed order of application of these compounds—that is, first promoter, then initiator—does not produce tumors.
Both exogenous and endogenous agents that function at this stage are referred to as tumor promoters.

12. Tumor promoters in general show organ-specific effects, e.g.,
Tumor promoters are
not mutagenic and generally are not able to induce tumors by themselves; rather they act through several mechanisms involving gene expression changes that result in sustained cell proliferation, either through increases in cell proliferation and/or the inhibition of apoptosis.
Nongenotoxic carcinogens frequently function at the tumor promotion stage. The growth of preneoplastic lesions requires repeated applications of or continuous exposure to tumor-promoting compounds.
Tumor promoters in general show organ-specific effects, e.g.,
a tumor promoter of the liver, such as phenobarbital will not function as a tumor promoter in the skin or other tissues.

13. Externally caused rather than
 Resulting from conditions within
 the  organism rather  than externally caused.
Externally caused rather than
 resulting from conditions within the organism.

14. Progression
Tumor progression is the third and last phase in tumor development. This phase is characterised by increased growth speed and invasiveness of the tumor cells. As a result of the progression, phenotypical changes occur.
the progression stage is an irreversible stage in that neoplasm formation, whether benign or malignant, occurs
The final stage of the carcinogenesis process, progression, involves the conversion of preneoplastic lesions into neoplastic cancer.
chemicals that function as progressor agents are usually capable of causing chromosomal abnormalities.

15. Progression cont……
In this stage, due to increase in DNA synthesis cell proliferation in the preneoplastic lesions, additional genotoxic events may occur resulting in additional DNA damage including chromosomal aberrations and translocations.

16. Complete carcinogens have the ability to function at the initiation, promotion, and progression stages and hence by definition have genotoxic properties.

19. carcinogen
A substance capable of causing cancer in living tissue.
A carcinogen is an agent, chemical or physical, that causes or induces neoplasia.
Carcinogens can be chemicals, viruses, hormones, radiation,or solid materials.
Genotoxic
Nongenotoxic (epigenetic)

20. Carcinogen cont…..
Genotoxic, meaning that they interact physically with DNA to damage or change its structure.

21. DNA adduct is a piece of DNA covalently bonded to a (cancer-causing) chemical. This process could be the start of a cancerous cell, or carcinogenesis

23. Carcinogen cont…..
Nongenotoxic (epigenetics) carcinogens are agents that do not directly interact with DNA and are believed to enhance tumor development by affecting gene expression

25. History of Chemical Carcinogenesis
Large numbers of chemicals were tested for carcinogenic potential in the s
Maximum Tolerated Doses (MTD) were used.
60% of carcinogens were genotoxic
40% of carcinogens were nongenotoxic
Some chemicals were single site, single species carcinogens
Others were multisite, multispecies carcinogens

26. Squamous cell carcinoma
polycyclic aromatic hydrocarbons

27. Toxic Effects of Hydrocarbons and Alcohols

28. Polycyclic aromatic hydrocarbons (PAHs)
Aliphatic Hydrocarbons:
Non-Halogenated (Hexane)
Halogenated:
Chlorinated Hydrocarbons (Trichloroethylene)
Brominated Hydrocarbons (Halothane)
Fluorinated Hydrocarbons (Methoxyflurane)
Cyclic Hydrocarbons (Cyclohexane)
Alcohols (Ethanol)

29. The first chemically identified carcinogens
Polycyclic Aromatic Hydrocarbons: Benzo(a)pyrine
The first chemically identified carcinogens
PAHs are one of the most widespread organic pollutants. In addition to their presence in fossil fuels they are also formed by incomplete combustion of carbon-containing fuels such as wood, coal, diesel, fat, tobacco .they are common environmental contaminants.
The PAHs are chemically inert, and require metabolism to exert their biologic effects

30. Polycyclic Aromatic Hydrocarbons: Benzo(a)pyrine con…..
Absorption
In humans, the major routes of uptake of PAH are thought to be through
the lungs and the respiratory tract after inhalation of PAH-containing aerosols or of particulates to which a PAH, in the solid state, has become to be absorbed
the gastro-intestinal tract after ingestion of contaminated food or water
the skin as a result of contact with PAH-bearing materials.
Distribution
Owing to the high lipophilicity of this class of compounds, their bioavailability after ingestion and inhalation must be considered to be significant:
detectable levels of PAH occur in almost all internal organs,
organs rich in adipose tissue can serve as storage depots from which the hydrocarbons are gradually released,
the GI tract contains high levels of hydrocarbon and metabolites, even when PAH are administered by other routes, as a result of mucociliary clearance and swallowing or hepatobiliary excretion.

31. Metabolism of benzo(a)pyrene
This is a multi-step process, it involves the following:
The first reaction is an epoxidation. initial epoxidation (cytochrome P450, CYP1A1 is an inducible enzyme),
The secend reaction is an hydration. 7,8-epoxide, is the subject of epoxide hydrolases to form stereoisomeric dihydrodiols.

32. Metabolism of benzo(a)pyrene cont….
dihydrodiols are converted further to the 7,8-dihydrodiol-9,10-epoxide.
The terminal oxidase is cytochrome P-450 (CYP1A1).
The diol epoxide can exist in 4 stereoisomeric forms of which the key carcinogenic product is benzo(a)pyrene-r-7,t-8-diol-t-9,10-epoxide.
The arene ring of benzo[a]pyrene-7,8-diol 9,10-oxide opens spontaneously at the 10 position, giving a highly reactive carbonium ion that can form a covalent addition product (i.e., adduct) with cellular macromolecules, including DNA

33. Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 super family of enzymes
inducible Enzyme: An enzyme that is normally present in minute quantities within a cell, but whose concentration increases dramatically when a substrate compound is added
Epoxide: consisting of, or containing an oxygen atom joined to two different groups that are themselves joined to other groups

34. Schematic diagram showing the mechanism through which exposure to polycyclic aromatic hydrocarbons is thought to cause cancer
Rundle, Mutat Res 600(1-2): (2006)

35. Several DNA-adducts can be formed, the most abundant being at the exocyclic amino group of deoxyguanosine ([7R]-N2-[10-{7,8,9-trihydroxy-7,8,9,10-tetrahydro-benz[a]pyrene} yl] - deoxyguanosine; BPdG) (B)

36. Cancer Classification :
PAHs are likely carcinogenic to humans based on sufficient evidence of carcinogenicity from studies in experimental animals.
Human studies: There is inadequate evidence for the carcinogenicity of PAHs in humans. Workers exposed to
numerous PAHs developed skin tumors. Dermal exposure to coal tar containing PAHs have been associated with increased incidences of skin tumors in humans
Exposures to other chemical mixtures that contain PAHs, such as cigarette smoke, coal tar and have been associated with increased incidences of lung cancer in humans.
experimental animals:
Target organs (sites): stomach, lung, liver, skin, mammary gland