Cumulative risk

Individuals with chronic hepatitis B have a high risk to develop cirrhosis and, once cirrhosis is present, the 5-year cumulative risk to develop hepatocellular carcinoma is about 10-15% (Fattovich et al. 2004). 

Organophosphate Pesticides Revised OP Cumulative Risk Assessment USEPA, Washington, DC (2002). Also available ontheWorld Wide Web http //www.epa.gov/pesticides/cumulative/ rra-op/, accessed September 2002. 

The then-current pesticide exposure data and risk assessment models failed to reflect real world exposures and risks. Deficiencies can only be rectified by carrying out cumulative risk assessments (CRA) across all... 

EPA released the first case study of cumulative risks from 24 OPs in food for scientific review in mid-2000. Public comments were solicited and several scientific panel (SAP) meetings were held on various aspects of EPA s quantitative methods. In December 2001 a preliminary OP-CRA (cumulative risk assessment) was released, this time encompassing 30 OPs, additional foods, more residue data and all major routes of exposure. Public comments were solicited again and another series of SAP meetings were held. The revised final OP-CRA was issued in June 2002 after more than 20 SAP meetings and four rounds of public comment (US Environmental Protection Agency, 2002). It is the most sophisticated and data-rich pesticide risk assessment ever carried out. 

US Environmental Protection Agency (20002). OPP Revised OP Risk Assessment -Cumulative Risk From Pesticides in Foods. l.C.l—1.C.24. 

The rate of detoxification of these agents by the body is not known. However, because of the cellular damage caused by these agents, exposures have a cumulative risk. 

Implications of the Food Quality Protection Act Common Mechanism of Toxicity and Cumulative Risk Assessment... 

Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargent D, Stevens JT, Weiner ML (2002) Mechanisms of pyrethroid neurotoxicity implications for cumulative risk assessment. Toxicology 171 3-59... 

More sophisticated probabilistic models are used by EPA to comply with the aggregate and cumulative risk provisions of the FQPA. These models consider rolling windows of exposure, toxicological equivalence factors for pesticides that have common toxicological mechanisms, and include methods to incorporate exposure from drinking water and residential pesticide use into the pesticide exposure estimates. 

Common Mechanism of Action Cumulative Risk Assessment by Dose Addition... 

The approaches discussed are the hazard index (HI) (Section 10.5.1.1) and the weight-of-evidence (WOE) modification to the HI (Section 10.5.1.2), the point of departure index (PODl) (Section 10.5.1.3), toxicity equivalency factors (TEFs) (Section 10.5.1.4), the margin of exposure (MOE) procedures (Section 10.5.1.5), and the cumulative risk index (CRl) method (Section 10.5.1.6). 

Although the HI method is transparent, easily understandable, and directly relates to the RfD, the major disadvantage is that the RfD is not an appropriate metric to use as a POD for cumulative risk assessment, since the RfD is normally derived by using NOAELs and uncertainty factors, which are not data based, but may incorporate significant policy-driven assumptions. This issue is addressed in detail in Chapter 5. 

The MOE approach is often used to determine the acceptability of acute risks for single chemicals and MOEs of >100 or >10 are usually considered acceptable when derived from toxicological data from animal and human studies, respectively. The US-EPA favors this concept for performing aggregate and cumulative risk assessments (Whalan and Pettigrew 1997). 

The cumulative risk index (CRI), also referred to as the aggregate risk index (ARI) has been suggested by the US-EPA (Whalan and Pettigrew 1997) to combine MOEs for chemicals with different AFs. The risk index (RI) of a chemical is the MOE divided by the AF or simply the reference dose divided by exposure, and is the reciprocal of the HQ ... 

US-EPA. 2000a. Proposed guidance on cumulative risk assessment of pesticide chemicals that has a common mechanism of toxicity. Public comment draft., June 22. Washington, DC U.S. Environmental Protection Agency, Office of Pesticide Programs. 

In clinical trials the cumulative risk of death 35 days after starting treatment was 9% in the lepirudin-treated patients, compared with 18% in historical controls cumulative risk of new thromboembolic complications was 6% with lepirudin and 22% in historical controls... 

E. Therapeutic response Thrombin-dependent tests show dose dependency [aPTT rise proportionally to dose of Refludan]. The key criteria of efficacy in two pivotal clinical trials from a laboratory standpoint were platelet recovery and effective anticoagulation. Seven days after the start of treatment with Refludan in patients with HIT, the cumulative risk of death, limb amputation, or new thromboembolic complication was substantially lower than in a historical control group. 

Soderlund DM et al Mechanisms of pyrethroid neurotoxicity Implications for cumulative risk assessment. Toxicology 2002 171 3. [PMID 11812616]... 

USEPA (2007) Triazine Cumulative Risk Assessment and Atrazine, Simazine and Propazine Decisions June 22, 2006, 6 September 2007 update http //www.epa. gov/oppsrrd 1 /cumulative/triazine fs. htm (last accessed 30 April 2010). 

All these assessments will provide information for comparing the risks associated with the modified baseline process with those associated with other alternatives. The Stockpile Committee previously recommended that the primary criterion for the selection of technology should be the minimization of cumulative adverse consequences from all relevant risks (NRC, 1994). Cumulative risks include risks to the public and workers, as well as the economic and sched-... 

The 1996 FQPA has also mandated that the EPA should also consider implementing cumulative risk assessments for pesticides. Cumulative risk assessments usually involve... 

More than 50% of patients with cerebral embolism have atrial fibrillation. In the majority of these patients, the underlying cardiac disease is nonvalvular. The risk of ischemic stroke and atrial fibrillation increases with age, reaching a cumulative risk of 35% during a patient s lifetime. Combined results from several randomized trials show that warfarin reduces the risk of stroke in patients with nonrheumatic atrial fibrillation by 68% (to 1.4% per year), with an excess incidence of major hemorrhage (including intracranial) of only 0.3% per year. 

It can assess risks posed by multiple exposures. Large-scale biomonitoring studies illustrate the need for developing cumulative risk-assessment approaches for biomonitoring data because exposures are typically to mixtures rather than to single toxicants. An examination of the Third National Report on Human Exposure to Environmental Chemicals, for example,... 

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