Toxicology: Understanding the Effects of Toxic Substances on Living Organisms

Posted on Apr 26, 2024 in Biology

Genetic Toxicology

Genetic toxicology analyzes the effects of toxic substances (chemicals, physical phenomena, or biological agents like retroviruses) on DNA and cellular genetic processes. There is a close relationship between mutations and cancer.

Mutagenesis and Genotoxicity

Mutagenesis or genotoxicity refers to alterations in DNA that are stable and transmissible during cell division (mitosis or meiosis). These alterations can occur in both germ cells and somatic cells, with different consequences:

Germ Cells

Mutations in germ cells are heritable and expressed when the mutant gene is present in both parents. These mutations occur during meiosis.

Somatic Cells

Mutations in somatic cells are not heritable. They can be caused by mutations in proto-oncogenes or tumor suppressor genes, which accelerate cell division and increase the likelihood of further mutations. The accumulation of mutations can lead to abnormal cell growth and cancer.

Consequences of Mutations

  • Abnormal cell growth and cancer (somatic cells)
  • Hereditary pathologies (germ cells)
  • Increased susceptibility to certain diseases
  • Congenital malformations

Types of Mutagenic Substances

  • Genotoxic substances: Directly affect nucleotides in DNA, causing genotoxicity.
  • Intercalating agents: Ethidium bromide, acridines.
  • Agents reacting with DNA: Hydroxylamine, alkylating agents, nitrous acid.
  • Base analogs: Guanine or thymine analogs.

Classification of Mutations

Mutations can be classified based on their mechanism, size, and nature:

a. Mechanism

  • Direct mutations: Genotoxic substances directly affect nitrogenous base pairs in nucleotides.
  • Indirect mutations: Failures in cellular growth control mechanisms (e.g., tumor suppressor genes).

b. Size

Mutations can be spontaneous or induced and may be reversible.

b.1 Point Mutations or Gene Mutations

Affect only a few nitrogenous bases in DNA and may not be visible in the phenotype.

  • Substitution: Does not alter the genetic charge. One base is replaced by another. Can be transitional (purine to purine) or transversional (purine to pyrimidine or vice versa).
  • Frameshift: Alters the genetic charge. One or more bases are lost (deletion) or added (insertion).
b.2 Chromosomal Mutations

Affect a large number of nitrogenous bases or an entire chromosome, often with serious consequences for the phenotype.

  • Numerical mutations: Addition or loss of chromosomes in daughter cells due to inhibition of chromosome division (anaphase). Can result in aneuploidy (affecting one chromosome) or polyploidy (affecting a group of chromosomes).
  • Structural mutations: Alterations in the structure of chromatids (DNA).

c. Nature

  • Spontaneous mutations: Occur naturally due to the complexity of cell division.
  • Induced mutations: Caused by human activity or exposure to genotoxic substances.

Chemical Carcinogenesis

Chemical carcinogenesis is the process by which exposure to certain chemicals can lead to the development of cancer. This process typically requires high doses and prolonged exposure and involves two key events: the formation of an initiated (mutated) cell and its proliferation to form a neoplasm.

Relationship Between Cancer and Mutation

Mutations play a crucial role in the early stages of cancer development. Chromosomal instability increases susceptibility to cancer, and chromosomal mutations can interact with pre-existing mutations. There is a strong correlation between mutagenesis and carcinogenesis caused by toxic substances.

Carcinogenesis Factors Associated with Lifestyle

  • Alcohol: Liver, esophagus, larynx cancer
  • Tobacco: Mouth, larynx, lungs, bladder cancer
  • Nitrosamines and ethanolamines: Liver, kidney, nasal cancer
  • Diet (high protein, high calorie, low antioxidant): Colon, gallbladder, endometrium cancer
  • Betel chewing: Mouth cancer

Carcinogenesis Associated with Medical Therapy and Diagnosis

  • Estrogens: Liver, endometrium cancer
  • Phenacetin: Renal carcinoma
  • Phenytoin: Lymphoma
  • Diethylstilbestrol: Vaginal cancer
  • Chloramphenicol: Leukemia
  • Azathioprine: Lymphoma
  • Alkylating agents: Bladder, leukemia

Cancer

Cancer is a disease characterized by uncontrolled cell growth and proliferation, often leading to the formation of tumors. It is a major cause of death worldwide.

Causes of Cancer

  • Ionizing radiation
  • Chemicals (genotoxic substances)
  • Biological agents (e.g., retroviruses)

Terminology

  • Neoplasia: New growth of tissue.
  • Benign: Non-invasive, slow-growing tumors that do not spread to other tissues.
  • Malignant: Invasive tumors that can spread to other tissues (metastasis).
  • Metastasis: The spread of cancer cells to other parts of the body.
  • Tumor: An abnormal mass of tissue.
  • Cancer: A malignant neoplasm.
  • Carcinogen: A substance that can cause cancer.
  • Genotoxic: A carcinogen that interacts with DNA, causing mutations or genotoxicity.
  • Non-genotoxic: A carcinogen that modifies gene expression without directly affecting DNA.

Stages of Cancer Development

Cancer development typically involves three stages:

1. Initiation

The first stage involves a rapid and irreversible process of mutation induction by a genotoxic carcinogen. A normal cell is converted into an initiated cell, which may or may not be malignant.

2. Promotion

The initiated cells undergo clonal proliferation, forming a benign preneoplastic focal lesion. This stage is reversible if the promoting agent is removed.

3. Progression

The benign preneoplastic lesion progresses to a neoplastic cancer, which may be benign or malignant. This stage is irreversible and may involve metastasis.

Developmental Toxicology

Developmental toxicology studies the effects of exposure to agents or conditions that disrupt normal development, leading to anatomical, mental, or functional defects. This field includes teratology, the study of structural birth defects.

Teratogenesis

Teratogenesis is the process by which birth defects occur due to exposure to teratogens (toxic agents). Two important lessons learned from teratology are the importance of clinical trials and the risks of using drugs for purposes other than those for which they were tested.

Examples of Teratogens

  • Thalidomide: Caused limb malformations, ocular, renal, and intestinal abnormalities, and congenital heart disease.
  • Diethylstilbestrol (DES): A synthetic estrogen that caused genital abnormalities and increased cancer risk in daughters and reproductive tract abnormalities in sons.
  • Ethanol: Can cause fetal alcohol syndrome, characterized by growth retardation, facial malformations, neurological damage, and heart defects.
  • Tobacco: Can lead to congenital defects, premature birth, low birth weight, and cognitive and functional deficits in babies.
  • Angiotensin-converting enzyme inhibitors: Can cause fetal kidney damage.

Liver Toxicity

The liver plays a crucial role in detoxification and metabolism, making it susceptible to damage from toxic substances.

Liver Anatomy and Physiology

The liver is composed of functional units called hepatic lobules, which contain hepatocytes (liver cells). Blood flows through the liver via the portal vein and hepatic artery, and bile is secreted into bile ducts.

Mechanisms of Liver Toxicity

Toxic substances can damage the liver through various mechanisms, including:

  • Hepatocyte death (necrosis or apoptosis)
  • Fatty liver
  • Disruption of the cytoskeleton
  • Cholestasis (reduced bile flow)
  • Bile duct damage
  • Sinusoidal disorders
  • Fibrosis and cirrhosis
  • Neoplasms (liver cancer)

Kidney Toxicity

The kidneys are responsible for filtering waste products from the blood and maintaining fluid and electrolyte balance.

Kidney Anatomy and Physiology

The kidneys are composed of nephrons, which are the functional units of the kidney. Each nephron consists of a glomerulus (a network of capillaries) and a tubule.

Mechanisms of Kidney Toxicity

Toxic substances can damage the kidneys through various mechanisms, including:

  • Acute kidney injury: Abrupt decrease in kidney function.
  • Chronic kidney failure: Progressive deterioration of kidney function.

Specific Nephrotoxicants

  • Heavy metals (mercury, cadmium)
  • Mycotoxins
  • Halogenated hydrocarbons (chloroform, bromobenzene)
  • Therapeutic agents (acetaminophen, NSAIDs)
  • Aminoglycosides

Blood Toxicity

Hematotoxicology is the study of the adverse effects of chemicals on blood and blood cell production.

Hematopoiesis

Hematopoiesis is the process of blood cell formation, which occurs in the bone marrow.

Toxicity at the Hematopoietic Level

Toxic substances can affect blood cell production in various ways, including:

  • Inhibition of blood cell production (pancytopenia, aplastic anemia)
  • Megaloblastic changes
  • Sideroblastic anemia
  • Leukemias and lymphomas

Immunotoxicity

Immunotoxicity refers to the adverse effects of chemicals on the immune system.

Vaccines and Immunotoxicity

Vaccines can contain various ingredients, some of which have been associated with potential toxicity. However, the benefits of vaccination generally outweigh the risks.

Antitoxic Therapy

Antitoxic therapy aims to counteract the effects of toxic substances.

Antagonists and Antidotes

Antagonists and antidotes are substances that can reverse or oppose the toxic effects of xenobiotics (toxic substances).

  • Antagonists: Compete with xenobiotics for binding to receptors or interfere with their biochemical pathways.
  • Antidotes: Directly interact with xenobiotics to prevent or reverse their toxic effects.

Pesticides

Pesticides are chemicals used to control pests, such as insects, weeds, and rodents.

Types of Pesticides

  • Insecticides: Organophosphates, carbamates, pyrethroids, organochlorines
  • Herbicides: Chlorophenoxy compounds, bipyridyl compounds
  • Fungicides: Captan, folpet, dithiocarbamates
  • Rodenticides: Coumarin derivatives

Metal Toxicity

Metals can be toxic to living organisms, depending on the dose, route of exposure, and other factors.

Examples of Toxic Metals

  • Arsenic
  • Cadmium
  • Lead
  • Mercury
  • Nickel

Metals with Potential Toxicity

  • Copper
  • Iron
  • Zinc

Metals Related with Medical Therapy

  • Aluminum
  • Lithium
  • Platinum