“RISK ASESSMENT OF CHEMICALS GENERAL CONCEPTS” 5797 ‐ Food toxicology DEGREE IN PHARMACY Year 2013 ‐ 14 – First semester Professors: Eugenio Vilanova and Jorge Estévez Department: Applied Biology
Unidad de Toxicología y Seguridad Química RISK ASESSMENT OF CHEMICALS GENERAL CONCEPTS Eugenio Vilanova Gisbert Universidad Miguel Hernández De Elche Unidad de Toxicología. Instituto Bioingeniería http://tox.umh.es
Biological systems interact with thousands of substances in your environment: Exogenous substances
Exogenous substances Once absorbed some have ENDOGENOUS BILOGICAL FUNCTIONS (Nutrients, vitamins and essential elements) Others without endogenous biological function in our body, we call them : XENOBIOTICS
SOME numbers: Genes that encode proteins: prokaryotes: 2,000 insects: 7,000 higher animals: around 50,000 different enzymatic reactions in the cell: around 5000 Endogenous molecules Deifferent proteins in a cell: around 5,000 monomers of biopolymers and metabolic: around 5,000
EXOGENOUS MOLECULES with endogenous function: Essential nutrients: 31 molecules 9 amino acids, 10 trace minerals, 12 vitamins) Probably essential: 11 molecules Food components: some 10,000 (?) (considering only the monomers of biopolymers) XENOBIOTICS Xenobiotics of natural origin: ????? Several hundred thousands Industrial Xenobiotics: European register: >100,000 substances regular interaction: 10,000 substances
Biological systems have mechanisms to deal with the interaction with thousands of external molecules: •destruction of foreign macromolecules (digestion and immune system) •Some are used for endogenous functions (nutrients, vitamins, oligo elements) •Conversion to endogenous molecules (intermediary metabolism) • Elimination of Xenobiotics (xenobiotic metabolism) BUT...
CHEMICALS MECHANISM OF NERVOUS DETOXICATION SYSTEM (ADME) ELIMINATION DISPOSAL
CHEMICALS NERVOUS SYSTEM MECHANISM OF DETOXICATION ELIMINATION
Biological systems have mechanisms to deal with the interaction with thousands of external molecules: Interaction with xenobiotics are part of the normal physiology • Elimination of Xenobiotics (xenobiotic metabolism) BUT...
SOME Xenobiotics at low doses, in certain circumstances, can cause desired changes as a remedy of diseases: THERAPEUTIC OR PROPHYLACTIC EFFECTS in these circumstances we call: MEDICINES, PHARMACEUTICAL DRUGS
The XENOBITICS or their metabolites at doses greater than the capacity of detoxication and disposal can cause : adverse effects to the health of the individual or ecosystem: TOXIC EFFECTS. On these circumstances we call them: TOXIC SUBSTANCES • TOXICANTS • TOXINS • POISONS …
SOME Xenobiotics in certain circumstances can selectively kill a way of life "while" respecting others: biocidal effects In these circumstances we call: • BIOCIDES (general concept or specific regulatory concept) • PESTICIDES (insecticides, herbicides, fungicides, rodenticides,...) • ANTIBIOTICS • DISINFECTANT • PLANT PROTECTORS BUT ...
ALL BIOACTIVE SUBSTANCE REPRESENTS A HEALTH RISK TO NON-TARGET SPECIES
TOXICOLOGY From the classic (archaic?) concept of study of the poison up to The current concept of • CHEMICAL SAFETY • risk assessment • risk prevention based on the modern science of Xenobiotics: molecular mechanisms of toxicity and biotransformation Conceptual analogy with Pharmacology but it is dealing with pharmaceutical drugs used for therapy
¿Why we need regulation internationally accepted ? ¿Métodos para hacer estos To: ensayos guaranty safety and confidence of the citizens (right to be safe and filling safe) guaranty free circulation of goods For that, harmonizing: Testing methods Criteria of evaluation Mutual acceptance
SOME BASIC PRINCIPLES: Priority: to guaranty safety of citizens The limits must not compromise other priority public health measures The proposal of a safety limit is a scientific process. Establishing a legal limit is a decision affected by other factors of technical viability and social sensitivity.
SOME CRITERIA for limits (1) SAFETY (1): based on a threshold. (2) (3) (4) (5) (6)
TOXIC EFFECT WITH THRESHOLD For most toxic effects (not all): are believed to have a “threshold”: dose below that no toxic effect is caused A threshold can be established NOAEL: “No observed adverse effect level” The highest tested dose with no effect
TOXIC EFFECT WITH THRESHOLD EFFECT NOAEL Log (D O S IS )
EVALUATION TOXICITY Acute toxicity. Determinacion DL50 . Toxicidad aguda por via oral, dérmica y por inhalación Irritación cutánea y, en caso necesario. ocular. Se hará si no es corrosivo. Sensibilidad cutánea. SHORT TERM (28 DAYS) Toxicidad oral a dosis repetitivas (estudio de 28 días). No si hay estudio a 90 días Otras vías (inhalación, dérmica, según proceda). SUBCRONIC TOXICITY. Estudio via oral durante 90 días . Otras vías si procede. CRONIC TOXICITY (2 years) Toxicidad oral a largo plazo (2 AÑOS) Carcinogenicidad (2 años) GENOTOXICITY . Mutagenicidad invitro Genotoxicidad in vivo. . REPRODUCTION TOXICITY. T eratogenicidad . Reproduccion a multiples generaciones Fertilidad y desarrollo. METABOLISM Absorción, distribución y excreción , tras la administración tanto oral como dérmica. Metabolismo. ESTUDIOS ADICIONALES Neurotoxicidad . Neurotoxicidad retardada en gallinas adultas. Metabolismo en vegetales (para agroquímicos) Efectos tóxicos de metabolitos procedentes de vegetales. Estudios de mecanismos para clarificar los efectos detectados. Efectos tóxicos sobre el ganado y los animales domésticos. HUMAN DATA Datos existentes de exposición humana epidemiológicos Estudios copn voluntarios Métodos de diagnóstico y tratamiento. RESUMEN de toxicología en los mamíferos y CONCLUSIONES. Resumen de toxicología en los mamíferos y conclusiones. Propuesta de NOAEL, IDA, AOAEL y otros parámetros. Evaluación global de los datos toxicológicos.
ESTABLishing the lowest relevant NOAEL Estudy NOAEL Subacute dermal (28 dias) 110 mg/Kg/day Subchronic dermal (90 days) in dogs 35 mg/Kg/day Subchronic oral 90 days in rats 50 mg/Kg/day Subchronic oral 1 year dogs 25 mg/Kg/day Chronic-carcinogenicity oral (2 years) in rat (systemic 10 mg/Kg/day effects) Reproduction 3 generation oral in rats (systemic 25 mg/Kg/day maternal effects) Teratogenicity in rabbit (10 days, GD 6-16) (systemic 50 mg/Kg/day maternal effects) … AND OTHER STUDIES AS REQUIRED FOR REGISTRATION) Lowest relevant NOAEL: 10 mg/Kg/day "The NOAEL is established as 10 mg/Kg/day on the basis of decrease in the body weight gain observed at the next higher tested dose in a 2 year oral study in rat
ACCEPTABLE DAILY INTAKE (ADI) Equivalent concepts: Reference dose (RfD), Acceptable exposure level (AEL), Tolerable daily intake, (Other) A DOSE WE CAN CONSIDER THAT HUMAN POPULATION CAN BE EXPOSED FOR LIFE WITHOUT RISK NOAEL is usually obtained from animal experimentation We need extrapolation to human We need to consider the interindividual variability in the sensitivity We need a safety factor for NOAEL (SAFETY FACTOR) ADI
SAFERTY FACTOR Other names: “uncertainty factor “(UF) “assessment factor” (AF) INTERSPECIES INTER INDIVIDUAL DIFFERENCES HUMAN DIFFERENCES KINETIC KINETIC DINAMIC DINAMIC KINETIC From Cassaret y Doull, Principals in Toxicology, 2005
SAFETY FACTOR (Uncertainty factor, UF) (Assessment factor, AF) 10 x extrapolation frm animal tohuman 10 x for human interindividual variability Usually UF= 100 Possible additional factors: • 3 x when NOAEL is from subchronic study indeed of chronic • N x if other uncertainties are observed (2x, 3x, or 10x). Then UF may be 200x, 300x, 1000x
Proposal of a limit in water (substance with threshold) We need: To know the toxicological properties and to establish: 1. Estimate a ADI from the NOAEL and a safety factor for an adult 2. Establish the standard water consumption: ( 2 Litres /day in adults of 60-70 Kg bw ) (1.5 L/d children of 30 Kg bw) (1 L/d infants 10 Kg bw) 3. Allocation in water: proportion of the ADI we accept to be exposed via drinking water (usually <10% of the ADI)
MAC LIMIT OR ALLOWABLE MAXIMUM CONCENTRATION IN WATER: CONCENTRATION THAT WOULD PROVIDE 10% OF THE MAXIMUM DAILY INTAKE IN 2 LITERS OF WATER ADI x (%contribution from water ) MAC = Daily intake For example in drinking water, it is assumed: Estimated consumption : 2 liters / person / day Contribution: 10% of the intake is due to the drinking water. It is assumed that the food is also contaminated and may provide 90% of the maximum permitted intake ADI x 10 MAC = mg/L 100 x 2L NOAEL (mg/Kg/day) x 70 (60) Kg body weight/person x 10/100 Contribution (mg/Litre) UF (10-100-1000) x 2 Litre /day NOAEL x 70 (60) (mg/Litre) UF x 2 x 10
EXAMPLE: A PESTICIDE for post-harvest thiabendazol, NOAEL =10 mg /Kg/day UF = 100. ADI = NOAEL/UF =10/100 = 0,1 mg/Kg/day For adult of 60 Kg bw = 0.1x60= 6 mg/day Recommended limit (under tox criteria): <10% ADI: 6*10/100= 0.6 mg Assuming 2L consumption: =0,6/2 = 0,3 mg/L = 300 ug/L
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