Tolerance assessments

Purpose Safety Pharmacology (pharmacokinetics, side effects tolerance assessment, evidence of toxicity, pharmacodynamics) Subjects 10-100 usually healthy males Duration <1 year... 

Hemodynamic parameters should be routinely monitored to assess drug tolerance. Assess blood pressure at baseline, after drug initiation and dose titration, then periodically thereafter in patients treated with fk-blockers, CCBs, nitrates, ACE inhibitors, and/or ARBs. 

F.-X. Mathy, A.-R. Denet, B. Vroman, P. Clarys, A. Barel, R. Verbeeck, and V. Preat. In vivo tolerance assessment of skin after insertion of subcutaneous and cutaneous microdialysis probes in the rat. Skin Pharmacol. Physiol. 16 18-27 (2003). 

Felt, O., et al. 1999. Topical use of chitosan in ophthalmology tolerance assessment and evaluation of precorneal retention. Int J Pharm 180 185. 

Local tolerance assessments are usually incorporated into repeat-dose toxicity studies. Specific assessments include clinical observations (e.g.,Draize scoring) and macroscopic and microscopic evaluations of the injection site. These types of studies may also be used to test formulation changes during the course of clinical development. 

The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup have been studied in 161 children aged 2-5 years (3). A single-dose open study was performed to characterize the pharmacokinetic profiles of loratadine and its metabolite desloratadine, and a randomized, double-bUnd, placebo-controlled, parallel-group study was performed to assess the tolerability of loratadine syrup 5 mg after multiple doses. Electrocardiographic parameters were not altered by loratadine compared with placebo. There were no clinically important changes in other tolerability assessments. 

The EPA should develop improved tools and methods to more systematically estimate the overall impact of prospective regulatory actions on health, the environment, and food production. Rapid advances in computer technology, as well as the EPA s successful efforts to computerize major data sets like the Tolerance Assessment System (TAS) make such progress readily attainable."... 

The last recommendation constituted NAS s endorsement of the EPA tolerance assessment system (TAS). The TAS is a computer-based system that can analyze risks based on various use patterns for pesticides. The system greatly improves the precision of the dietary exposure assessment. TAS is already being used by EPA and provided the tools used by the NAS in its own risk analyses. 

Felt, O., Furrer, P., Mayer, J. M., Plazonnet, B., Buri, R, and Gurny, R. 1999. Topical use of chitosan in ophthalmology Tolerance assessment and evaluation of precorneal retention. Int. J. Pharm. 180 185-193. 

From the risk tolerability assessment, it follows which safety relevant scenario(s) contribute(s) most to the expected value and the 95% confidence interval of the risks that has been qualified as being not below the TLS. For each safety relevant scenario the hazards or conditions that contribute most to the high risk level or confidence interval are identified and localised during step 7. These are referred to as the safety bottlenecks. If desired, this may also be done for assessed risk levels that are just below the TLS. The identification and localisation of safety bottlenecks is important as it gives operational concept designers directions for searching potential risk... 

Mills PC, Ahlstrom L, Wilson W (2005) Ototoxicity and tolerance assessment of a TrisEDTA and polyhexamethylene biguanide ear flush formulation in dogs. J Vet Pharmacol Ther 28 (4) 391-397. doi 10.1111/j. 1365-2885.2005.00672.x Mozayani A, Raymon L (2004) Handbook of drug interactions a clinical and forensic guide. Humana Press, Totowa... 

Secondly, a probabilistic (Monte Carlo) simulation was used. This considers a complete set of crop residue data and samples data points randomly. This approach is generally considered to be more Realistic for assessing dietary exposure to a pesticide. Tolerance assessments used TAS and DEEM in order to establish the safety of tolerances (MRLs or maximum residue limits) for cotton, potato and tomato and also to compare the output of the two programs. 

An acute tolerance (MRL) assessment is routinely conducted by DPR to ensure that this level of residue will not result in adverse effects in consumers of treated commodities. It is the maximum amount of a pesticide residue dut is legally allowed on that commodity (14). By definition, the use of tolerance residue levels means that a point estimate, deterministic approach was used. DPR considers that acute, but not chronic, tolerance assessment is appropriate because it is highly improbable that an individual would consume a commodity with tolerance level residues on a chronic, annual basis. Similarly, it is considered by DPR to be inappropriate to use a percent crop-treated (%CT) adjustment on the tolerance assessment, whenever using a deterministic approach (Table VI). These tolerance assessments determined the MOS values at the 95 percentile of exposure. 

Although chronic tolerance assessments are considered invalid by DPR, nonetheless USEPA conducts such investigations. Therefore, chronic tolerance evaluations were conducted for tomato for comparative purposes. Using the annualized mean dietary exposure (DEEM ), and the 1-yr. dog NOEL of 0.02 mg/kg/day, MOS values of 11 (children 1-6 yr) to 136 (nursing infants) were obtained. These corresponded to consumption of 0.IS - 1.80 pg/kg/day. All population groups except nursing infants had MOS values below 100 from chronic dietary exposure to tolerance level residues of methamidophos on tomato. 

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