Unit 1

What is toxicology?

The study of the effects of xenobiotics on living ecosystems, including the body.

What are xenobiotics?

Substances that are foreign to the body, such as alcohol, drugs, and environmental contaminants.

What is the primary route of xenobiotic exposure?

Oral/Gastrointestinal exposure.

What can excessive intake of nutrients cause?

Adverse effects in the body, potentially acting as xenobiotics.

Who is known as the father of toxicology?

Paracelsus.

What does the phrase 'the dose makes the poison' imply?

That the right dose differentiates a poison from a remedy.

What are some examples of microbiological xenobiotics?

Salmonella and botulinum toxin.

What is the effect of nutritional status on xenobiotic metabolism?

Nutritional deficiencies can alter how the body metabolizes xenobiotics.

How can xenobiotic exposure affect nutritional status?

For example, alcohol consumption can lead to vitamin A deficiency.

What are Persistent Organic Pollutants (POPs)?

Environmental xenobiotics such as mercury, PCBs, and dioxins.

What is bioaccumulation?

The build-up of toxins in an organism over time.

What is biomagnification?

The increase in toxin concentration as it moves up the food chain.

What can excessive protein intake lead to?

Renal dysfunction and increased risk of bone fractures.

What is the relationship between over-nutrition and obesity?

Habitual over-nutrition can lead to obesity and associated health risks.

What is botulism?

A serious illness caused by the botulinum toxin, leading to paralysis.

What are the three forms of botulism?

Foodborne, wound, and infant botulism.

What is the impact of excess calorie intake?

It can lead to obesity and increased risk of chronic diseases.

What does the term 'over-nutrition' refer to?

Excessive intake of nutrients leading to adverse health outcomes.

What are phytochemicals?

Natural compounds produced by plants that can act as xenobiotics.

What is the role of food additives in toxicology?

They can be sources of xenobiotic exposure if consumed in excess.

What is the effect of sulfur amino acid deficiency?

It can impact the metabolism of drugs like acetaminophen.

What is a key takeaway regarding xenobiotics?

One xenobiotic can have multiple possible adverse effects.

What are microplastics and nanoplastics (MNPs)?

Small plastic particles encountered by humans and organisms through ingestion, inhalation, and contact.

What is DDT and its primary use?

DDT (Dichlorodiphenyltrichloroethane) is an insecticide used to reduce malaria risk.

What is a consequence of DDT use regarding mosquito species?

Many mosquito species have developed resistance, making DDT less effective.

What are the health effects of DDT exposure in humans?

Liver damage, including liver cancer, nervous system damage, congenital disabilities, and reproductive dysfunction.

What is the significance of DDT in terms of transgenerational health effects?

DDT can induce epigenetic transgenerational inheritance of obesity and various diseases.

What are polychlorinated biphenyls (PCBs)?

Organic chlorine compounds that are persistent in the environment and used in industrial materials.

What are the properties of PCBs?

PCBs are extremely persistent, lipophilic, and can accumulate in the food chain.

What is TCDD and its common name?

TCDD is 2,3,7,8-Tetrachlorodibenzo-p-dioxin, commonly referred to as dioxin.

What are the health risks associated with TCDD exposure?

Carcinogenic effects, teratogenic effects causing birth defects, and chloracne.

What is the half-life of TCDD in humans?

7-8 years.

What are Polycyclic Aromatic Hydrocarbons (PAHs)?

A class of carbon and hydrogen-containing molecules formed from incomplete combustion of organic materials.

How are PAHs formed in food processing?

They are produced during the cooking of meats and from burning organic materials.

What is Benzo[a]pyrene (BaP)?

A well-studied example of a PAH that is a known carcinogen.

What are Heterocyclic Amines (HCAs)?

Carcinogenic compounds formed when amino acids and sugars react at high temperatures during meat cooking.

What are nitrosamines and their association with cancer?

Carcinogenic compounds formed from nitrites and secondary amines, often found in cured meats.

What is the significance of lipophilic xenobiotics in the body?

They accumulate in lipid-rich tissues, increasing the risk of neurotoxicity and cancer.

What is the role of the liver in xenobiotic metabolism?

The liver metabolizes xenobiotics to convert them into water-soluble metabolites for excretion.

What are the phases of xenobiotic metabolism?

Phase 1 involves functionalization, and Phase 2 involves conjugation to create water-soluble metabolites.

What are the immediate risks of neurotoxicity from xenobiotics?

Adverse effects on brain and nervous system function, which may be permanent or reversible.

What is the relationship between PAH exposure and scrotal cancer?

Chimney sweeps exposed to PAHs during puberty had an increased incidence of scrotal cancer.

What is the impact of high cooking temperatures on nitrosamine formation?

High cooking temperatures enhance the formation of nitrosamines from nitrites.

What is the significance of the Great Lakes in relation to PCBs?

PCBs were detected in the Great Lakes in 1966, leading to a ban on their manufacturing by 1977.

What is the role of cytochrome P450 enzymes in xenobiotic metabolism?

They are involved in Phase 1 reactions to bioactivate xenobiotics, although this can be risky.

What are primary carcinogens?

Substances that can cause cancer by damaging DNA.

What is a reactive intermediate?

A product formed during Phase 1 metabolism that can cause mutations and cancer.

What is Phase 1 metabolism?

The initial metabolic process that converts lipophilic xenobiotics into reactive intermediates.

What is Phase 2 metabolism?

The process of conjugation that decreases reactivity and increases water solubility of xenobiotic metabolites.

What is the primary function of Phase 2 reactions?

To reduce the reactivity of metabolites and facilitate their excretion.

How do water-soluble xenobiotics enter the liver?

They cross the intestinal barrier into the liver via the hepatic portal vein (HPV).

What pathway do lipid-soluble xenobiotics follow to enter the bloodstream?

They are packaged into chylomicrons and enter the lymphatic system before reaching the blood.

What is the significance of the hepatic portal vein?

It carries nutrient-rich blood from the gastrointestinal tract to the liver for metabolism.

What is enterohepatic circulation (EHC)?

The recycling of bile acids and lipophilic xenobiotics between the liver and intestine.

What happens to lipophilic xenobiotics in the liver?

They can be metabolized or bound to bile for excretion.

What is the common bile duct's role in digestion?

It drains bile from the liver into the duodenum for lipid digestion.

What is the function of bile in relation to lipophilic xenobiotics?

Bile acts as an emulsifier, trapping lipophilic xenobiotics for excretion.

What is the first-pass metabolism?

The liver's initial opportunity to metabolize xenobiotics before they reach systemic circulation.

What is the role of sinusoids in the liver?

Sinusoids allow for the mixing of blood and facilitate the exchange of substances between blood and liver cells.

What are hepatocytes?

Liver cells responsible for metabolizing xenobiotics and producing bile.

What is the significance of reactive intermediates produced in Phase 1 reactions?

They can cause DNA damage, leading to mutations and cancer if not processed by Phase 2 reactions.

What happens to xenobiotics that are not metabolized in the liver?

They can enter the bloodstream and affect other tissues in the body.

What percentage of bile salts are reabsorbed in the intestine?

Approximately 95% of bile salts and bile acids are reabsorbed.

What is the fate of xenobiotics that are bound to bile in the intestine?

They can be reabsorbed and returned to the liver or excreted in feces.

What is the impact of liver expression of Phase 1 and Phase 2 enzymes on xenobiotic metabolism?

It determines the rate of metabolism and the potential for DNA damage.

What is the hepatic artery's role in liver blood supply?

It provides oxygenated blood to the liver, accounting for 20-25% of liver blood flow.

What happens to xenobiotics after they leave the liver?

They can enter the bloodstream, go to other tissues, or be excreted via urine or bile.

What is the role of bile canaliculi in the liver?

They transport bile from hepatocytes to the bile ducts for digestion.

What is the primary function of bile acids in digestion?

To emulsify fats, aiding in their digestion and absorption.

What is the primary organ that metabolizes xenobiotics?

The liver has the greatest metabolizing capacity for phase 1 and phase 2 reactions.

What are the three natural routes of xenobiotic exposure?

Topical (skin), inhalation (lungs), and per os (oral via GIT).

How does the liver contribute to the excretion of lipophilic xenobiotics?

The liver synthesizes bile, which acts as a route of excretion for lipophilic xenobiotics after first-pass metabolism.

What is the significance of first-pass metabolism?

First-pass metabolism occurs when substances absorbed via the gastrointestinal tract are metabolized in the liver before reaching systemic circulation.

How do hydrophilic xenobiotics get excreted?

Hydrophilic xenobiotics and their metabolites can be excreted in urine after passing through the liver.

What is the role of the lungs in xenobiotic exposure?

The lungs receive high concentrations of xenobiotics first, and they can undergo phase 1 and phase 2 reactions before distribution to other tissues.

What happens to xenobiotics that are large and lipophilic?

They are incorporated into chylomicrons in the GIT and circulate through the lymph before entering the bloodstream.

What is the exposure concentration of xenobiotics in the skin compared to the lungs?

The highest concentration of xenobiotics is encountered in the skin, followed by the lungs.

What is the function of the coronary arteries in relation to xenobiotic exposure?

The coronary arteries supply blood to the cardiac tissue, resulting in minimal exposure of the heart to xenobiotics.

What is the surface area of the lungs compared to the skin and GIT?

The surface area of the lungs is 75 m², while the skin is 2 m² and the gastrointestinal tract (GIT) is 200 m².

What is the significance of sublingual exposure to xenobiotics?

Sublingual exposure allows xenobiotics to enter systemic circulation directly, avoiding first-pass metabolism.

What is the process of xenobiotic distribution after entering systemic circulation?

Once in systemic circulation, xenobiotics are evenly distributed to all tissues, including the liver.

What are the implications of xenobiotic exposure via inhalation?

Inhalation leads to the highest concentration of xenobiotics in the lungs, with no first-pass metabolism and gradual clearance by the liver.

What is the fate of xenobiotics after they leave the liver?

Xenobiotics can either be trapped in enterohepatic circulation (EHC) or leave the liver via the hepatic vein to enter systemic circulation.

What are the implications of intravenous (i.v.) and intramuscular (i.m.) routes of xenobiotic exposure?

These routes are considered 'hospital' or 'experimental' and allow for direct entry into systemic circulation, bypassing first-pass metabolism.

What is the role of the gastrointestinal tract in xenobiotic metabolism?

The GIT has some capacity for phase 1 and phase 2 reactions, but the majority of metabolism occurs in the liver after first-pass.

How do xenobiotics interact with the kidney?

The kidney is involved in the metabolism and excretion of xenobiotics, particularly phase 2 products.

What is the significance of the thoracic duct in xenobiotic transport?

The thoracic duct allows chylomicrons containing lipophilic xenobiotics to enter the bloodstream from the lymphatic system.

What is the difference between topical and inhalation routes of xenobiotic exposure?

Topical exposure involves direct contact with the skin, while inhalation involves direct contact with the lungs.

What are the consequences of xenobiotic accumulation in lipid-rich tissues?

Xenobiotic accumulation can lead to neurotoxicity and other adverse effects.

What is the process of xenobiotic clearance after systemic circulation?

Xenobiotics are gradually cleared by the liver or other tissues with metabolic capacity.

What happens to xenobiotics that bind to bile in the small intestine?

They may travel directly to the liver via the hepatic portal vein (HPV) for metabolism.

What are chylomicrons (CM) and their role in lipophilic xenobiotic metabolism?

Chylomicrons are lipoprotein particles that package large lipophilic xenobiotics with dietary lipids, allowing them to travel through the lymphatic system to the heart and then to systemic circulation.

What happens to smaller-sized lipophilic xenobiotics in the body?

Smaller-sized xenobiotics can enter the hepatic portal vein directly to the liver for metabolism.

What is the significance of the hepatic portal vein (HPV) in xenobiotic metabolism?

The HPV brings deoxygenated, nutrient- and xenobiotic-rich blood from the gastrointestinal tract to the liver, allowing for screening and first-pass metabolism before reaching systemic circulation.

What are some examples of lipophilic xenobiotics that do not undergo first-pass metabolism?

Examples include PCBs, dioxins, and methyl mercury, which can accumulate in lipid-rich tissues and have long half-lives.

What are the potential health effects of dioxin accumulation in the body?

Dioxin accumulation can cause chloracne, neurotoxicity in the developing fetal brain, and cognitive dysfunction in adults.

How does the liver's structure contribute to its efficiency in xenobiotic metabolism?

The liver has sinusoids that allow nutrient- and xenobiotic-rich blood to mix and flow past hepatocytes, facilitating efficient metabolism.

What role do hepatocytes play in xenobiotic metabolism?

Hepatocytes are liver cells that contain enzymes for metabolizing nutrients and xenobiotics.

What is Olestra and its impact on lipophilic xenobiotic metabolism?

Olestra is a fat substitute that can bind to fat-soluble vitamins and xenobiotics, leading to their excretion and potentially preventing accumulation in the body.

Why is the liver resistant to carcinogenesis?

The liver has low levels of cell division, which reduces the chance of DNA damage and mutations, and it can repair DNA damage effectively.