THE KIDNEYS

Regulation of extracellular components.Elimination of waste products.

Regulation of acid-base balance.Erythropoietin production.

Formation of renin.Xenobiotics metabolism.

Production of glucose and 1,25-dioH vitamin D3.

ANATOMY OF KIDNEY

1. Renal vein2. Renal Artery3. Renal Calyx

4. Medullary Pyramid

5. Renal Cortex

6. Segmental Artery

7. Interlobar Artery

8. Arcuate Artery

9. Arcuate Vein

10. Interlobar Vein

11. Segmental Vein

12. Renal Column

13. Renal Papillae

14. Renal Pelvis

15. Ureter

NEPHRON

NEPHROTOXICANTS

Heavy metals accumulate in body Induction of metallothionein by liver. Cadmium (Cd) stimulates its

production. Metallothionein bind with Cd and

protects other organs from its toxic effects.

The kidney is vulnerable to this complex.

Beta-2-microglubulin excretion from kidney is diagnostic of Cd toxicity.

NEPHROTOXICANTS

Long term use of Analgesics Antibiotics. Anticancer drugs. Ochratoxin A.

Role of Immune System

IMMUNE SYSTEM

IMMUNOSUPRESSION BY TOXICANT

Pharmaceutical compounds.

Corticosteroids

Antitumor drugs

Cyclophosphamide

6-mercapto-purine

5-fluorouracil

Methotrexate

IMMUNOSUPRESSION BY TOXICANT

Halogenated Aromatic Hydrocarbons 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)

Lymphoid atrophy, Thymic involution. Polychlorinated biphenyls (PCBs) Polybrominated biphenyls (PBBs)

Suppress Antibody Response. Formaldehyde & Isocyanates

Types I and IV reactions

IMMUNOSUPRESSION BY TOXICANT

Polyaromatic hydrocarbons (PAHs)

Depress Humoral immunity , Cell mediated immunity and Tumor resistance.

Nitrosamines (dimethyl & diethyl nitrosamine)

inhibit T-cell dependent humoral immune response.

Pesticides Immunotoxic

METALS

As Arsenic immunosupressive

Be  Beryllium

T-cell mediated hypersensitivity

Cd Cadmium

Depression of humoral, macrophages

Hg Mercurry Type III hypersensitivity

Pb  Lead Susceptibility of upper respiratory infection

SKIN

SKIN

Physical protection from environmental agents Hydroregulation through active &passive mechanism Thermoregulation to maintain core body temperature. Chemical synthesis of vitamin D. Immunological surveillance and function. Absorption of pharmaceutical preparation. Sensory reception of pain, temperature, touch &

pressure

HOMEOSTATIC THERMOGENESIS

TOXICOLOGICAL POINT OF VIEW

Route of exposure for systemic toxicants. Direct target for toxicity. Xenobiotic metabolizing organ. Minor pathway for the elimination of certain

toxicants.

SKIN

Epidermis: outermost layer; mostly epithelial cells; non-vascular

Dermis: fibrous connective tissue; vascular

Hypodermis: (superficial fascia)not skin; protective; adipose and loose connective tissue

Epidermis is thick keratinized Stratified Squamous Epithelium consisting of four cell types and five layer

Keratinocytes

Melanocytes

Merkel cells

Langerhan’s cells

.

STRATUM BASALE (STRATUM GERMINATIVUM)—DEEPEST LAYER            I. SINGLE LAYER OF MITOTICALLY ACTIVE CELLS            II. GIVE RISE TO KERATINOCYTES (YOUNGEST)            III. INCLUDES MELANOCYTES AND SOME MERKEL CELLSSTRATUM SPINOSUM (PRICKLY LAYER)—WEBLIKE NETWORK OF CELLS FORMED BY INTERMEDIATE FILAMENTS ATTACHED TO DESMOSOMES            I. COMPRISED OF KERATINOCYTES            II. INCLUDES MELANIN GRANULES AND LANGERHANS CELLSSTRATUM GRANULOSUM—THICK; 3-5 CELL LAYERS; KERATINOCYTES ARE MODIFIED             I. FLATTENED; NUCLEI AND ORGANELLES LOST             II. KERATOHYLALINE AND LAMELLATED GRANULES ACCUMULATE III. LAMELLATED GRANULES ARE GLYCOPROTEINS, RELEASED INTO EXTRACELLULAR SPACE, THAT REDUCE WATER LOSS IV. CELLS MORE RESISTANT TO DESTRUCTION

Stratum Lucidum—a few rows of clear, flattened, dead keratinocytes; layer occurs only in thick skin i. Keratohyalin granules—gummy substance associated with keratin filaments ii. Cells aggregate in parallel arraysStratum Corneum (Horny layer)—outer most layer; most

of epidermis thickness             i. 20-30 cell layers thick ii. Keratin, thickened plasma membranes and glycoproteins protect against abrasion and loss of water iii. Cornified or horny cells—remnants of cells from this layer

MELANOCYTES

LANGERHANS CELLSANTIGEN

PRESENTATION.

MERKEL’S CELLSTOUCH RECEPTOR 

DERMIS

APPENDAGES OF THE SKIN

SEBACEOUS GLANDS

MEIBOMIAN GLAND

SWEAT GLANDS

SKIN ABSORPTION OF CHEMICALS

Percutaneous absorption: systemic toxicity from skin exposure can occur only when chemical moves from the epidermis into dermis of the skin, which contain blood vessel, the movement is by passive diffusion.

The major barrier is stratum corneum.The rate of penetration is largely related to the

lipophilicity of the chemical. (Lipophilic substances, Hydrophilic substances)

SYSTEMIC EFFECTS FROM PERCUTANEOUS ABSORPTION

Benzidine Bladder cancer

Hydrofluoric acid Electrolyte deregulation, Kidney

Aniline Bladder cancer

Acrylmide Peripheral neuropathy

Carbon disulfide Coronary artery disease, CNS

Glycol ether Aplastic anemia

Hexachlorophene Encephalopathy

Inorganic mercury Renal toxicity

Alkyl lead Neurotoxicity

Boric acid Gastrointestinal lesions

SKIN TOXICITY: LOCAL EFFECTS

Contact Dermatitis

Irritant contact dermatitis Allergic contact dermatitis Phtotoxic skin response.

EFFECTS OF CHEMICAL EXPOSURE ON SKIN

Urticarial reactions: Type I allergic reactions cause the release of

histamines, IgE, and local inflammatory mediators.

Cutaneous granulomas: Inflammatory response to insoluble materials.

Hair loss: due to exposure of thallium, cancer therapeutic agents, depilatories.

Hypopigmentation: inhibition/destruction of melanocytes (phenolic preparation, hydroquinone).

Hyperpigmentation: Heavy metals, acridines

Color change: orange/yellow from picric acid, green from copper dust, black from osmium trioxide.