1 / 44

Review of Human Lethality Estimates for Chlorine Inhalation

UNCLASSIFIED/UNLIMITED. Review of Human Lethality Estimates for Chlorine Inhalation. 13 January 2009. Douglas R. Sommerville John J. Bray Raymond E. Jablonski Sharon A. Reutter-Christy Erin E. Shelly. Eighth Symposium on the Urban Environment

patia
Download Presentation

Review of Human Lethality Estimates for Chlorine Inhalation

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. UNCLASSIFIED/UNLIMITED Review of Human Lethality Estimates for Chlorine Inhalation 13 January 2009 Douglas R. Sommerville John J. Bray Raymond E. Jablonski Sharon A. Reutter-Christy Erin E. Shelly Eighth Symposium on the Urban Environment 89th Annual American Meteorological Society Meeting Phoenix, AZ Distribution is Unlimited--Available for Public Release (PAO # 100804, 6 January 2009, US Army ECBC,ATTN: AMSRD-ECB-RT-IM, Aberdeen Proving Ground, MD. 21010-5424) DISCLAIMER: The findings presented in this briefing are not to be construed as an official Department of the Army or Department of Homeland Security position unless so designated by other authorizing documents. UNCLASSIFIED/UNLIMITED

  2. Acknowledgements • Work funded by the Chemical Security Analysis Center (CSAC), US Department of Homeland Security, Aberdeen Proving Ground, MD • Work documented in CSAC technical report • Report Number CBRNIAC-SS3-628, January 2008 • Authors are from following organizations • ECBC • CSAC • Optimetrics, Inc., Abingdon, MD UNCLASSIFIED/UNLIMITED

  3. Purpose and Application of Study • Reevaluate the human lethality estimate for chlorine inhalation exposure as a function of • exposure duration • population basis (military versus general population) • Estimates are to be used in risk assessments involving chlorine airborne releases • atmospheric transport and dispersion (ATD) models UNCLASSIFIED/UNLIMITED

  4. General Approach • Literature Review • Data collection and reduction of mammalian lethality data • Statistical analysis of mammalian lethality data • Modeling of relationship between subpopulation and general population • Application of Crosier (2007)—Available from DTIC, AD# A465827 • Brief description of Crosier Model shown in backup slides • Investigation of sensitivity of ATD model predictions to changes in toxicity estimate parameters UNCLASSIFIED/UNLIMITED

  5. Toxicity Parameters Investigated • Variability in human toxic response: kTL or kC • Probit slope with respect to toxic load or vapor concentration • Time dependence of toxicity: n • Toxic load exponent (TLE) • Toxic load = CnT • Median effective quantities • LCT50 – Lethal Concentration Time for 50% of individuals exposed • LTL50 – Lethal Toxic Load for 50% of individuals exposed UNCLASSIFIED/UNLIMITED

  6. Shallow versus Steep Probit Slopes UNCLASSIFIED/UNLIMITED

  7. Importance of Establishing the Time Dependence of Toxicity UNCLASSIFIED/UNLIMITED

  8. Literature Review • Identification of general references/sources • Previously reported human estimates • Existing mammalian lethality data • Historical record of industrial accidents involving chlorine UNCLASSIFIED/UNLIMITED

  9. General References/Sources used for Initial Identification of Chlorine Toxicity Studies • Acute Exposure Guideline Levels (AEGL) for Chlorine (2004) • Third Edition of Lees’ Loss Prevention in the Process Industries (Chapter 18: “Toxic Releases”) • Chlorine Toxicity Monograph (1988) published by the Major Hazards Assessment Panel • Edgewood CB Center Technical Library and Historical Research & Response Team UNCLASSIFIED/UNLIMITED

  10. Previous Human Lethality Estimates • Studies with estimates for median lethal dosage • US Coast Guard sponsored studies for Vulnerability Model • Eisenberg et al. (1975) • Perry and Articola (1980) • ten Berge and van Heemst (1983) • Rijnmond Report (1982)/Harris and Moses (1983) • Withers and Lees (1985) • Many existing estimates for threshold lethal dosages were not used for this analysis • Purpose was to determine median lethal dosage and probit slope (whole distribution) not just the tail of the distribution UNCLASSIFIED/UNLIMITED

  11. Existing Mammalian Lethality Data • Searched for experimentally measured median lethal dosages in mammals • Whenever possible, underlying response data were obtained • Used only studies where mammals were exposed for a specified period of time and then removed from the chamber for observation • Gas-until-death studies not used • Such studies generally produce higher median lethal dosages relative to fixed duration and observe studies • Example: the often cited Weedon et al. (1940) was not used in this study because it was a gas until death study • Median dosages not associated with a duration were not used UNCLASSIFIED/UNLIMITED

  12. Scope of Existing Mammalian Lethality Data • 29 individual median lethal inhalation dosages were found and/or calculated • Collected from 18 studies and sources dating back to 1882 • Eight mammalian species represented (mouse, rat, guinea pig, rabbit, cat, dog, sheep and goat) • Data discovered in previously “forgotten” US government technical reports • In some cases, LCT50 was not originally reported and was subsequently calculated in this study using the reported response data UNCLASSIFIED/UNLIMITED

  13. Median Lethal Dosage as a Function of Exposure Duration for Chlorine Inhalation UNCLASSIFIED/UNLIMITED

  14. Historical Record—Accidental Chlorine Releases • Accidental releases (up to 50 tons) • Fatalities (with one exception) occurred within about 400 meters of the actual point of release • Most fatalities occurred within 250 meters • Largest number of fatalities from a release is around 60 (Romania in 1939) • Marshall (1977) estimated that there are on average 0.3 to 0.8 fatalities per metric ton of an accidental industrial release UNCLASSIFIED/UNLIMITED

  15. Historical Record—Civilian Exposure (?) at Second Ypres (1915) • Marshall noted that there are no reported civilian casualties from the first wartime use of chlorine at the Second Battle of Ypres (1915) • Germans released 168 tons over 4 mile front • Civilians in Ypres were about 6 kms from the front UNCLASSIFIED/UNLIMITED

  16. Current ATD Model Predictions and the Historical Record • Current atmospheric transport & dispersion (ATD) model predictions more often than not greatly overestimate the downwind hazard from a chlorine release • Example: LC50 plume extending 650 to 1100 meters downwind for a 1000 kg release (Franks et al. (1996)) • Possible explanations • ATD models are over-predicting the downwind transport of chlorine • Inadequate knowledge of atmospheric chemistry of chlorine and/or heavy gas transport (?) • The human lethality estimates are over-predicting the toxicity • The point of the present study • Combination of both of the above factors UNCLASSIFIED/UNLIMITED

  17. Data Reduction • Probit slope and LCT50 from response data • Probit slope—from probit analysis • LCT50—from either probit analysis or maximum likelihood estimation (MLE) • Species properties—minute volume (VM) and body mass (M) • Obtained average values for non-anaesthetized mammals from Bide et al. (2000) • Convert inhalation dosages into nominal doses for allometric modeling • Detailed statistical analysis of individual studies for toxic load exponent estimate • Bitron and Aharonson (1978)—mouse lethality study UNCLASSIFIED/UNLIMITED

  18. Response Variance—Probit Slope Estimate • Response variance assumption: • Healthy lab animals [=] healthy (military) humans • Variance estimated via weighted average of experimental probit slopes • Slopes calculated from eight studies • Weights equal the inverse of the square of the standard error • Hence, less precise values had less influence on the final estimate • Average equals 7.96 (95% CI of 7.21 to 8.71)--rounded to 8.0 for subsequent calculations for the general population • This approach was not used by previous researchers in the derivation of their probit slope estimates UNCLASSIFIED/UNLIMITED

  19. Allometric Modeling Results • Lethality is a slight function of species body mass—LCT50 increases with body mass • Ratio of LCT50s • Man to Mouse = 2.25 • Man to Dog = 1.18 • Man to Goat = 1.07 • Allometric modeling was less useful for time dependence of lethality • Toxic load exponent equals 2.7 with 95% CI of 2.1 to 4.0 • Wide error bars are an issue • Chlorine is a not a Haber’s Rule chemical (n = 1), but what is the value of its toxic load exponent? UNCLASSIFIED/UNLIMITED

  20. Experimental Values of Chlorine Toxic Load Exponent from Previous Studies • Only two suitable lethality studies found with exposures at several exposure durations • Bitron and Aharonson (1978) 476 male mice • ten Berge and van Heemst calculations (1983) • n = 3.5 (95% CI of 2.5 to 4.5) • Based upon fit of LCT50 values • Present study re-calculation of n from Bitron and Aharonson data • n = 3.36 (95% CI of 2.99 to 3.73) • Based upon probit analysis of original binary response data • Zwart and Woutersen (1988) rats and mice (n is suspect) • Curvature in log(LCT50) versus log(T) plot (n < 1 for 5 to 30 minutes) UNCLASSIFIED/UNLIMITED

  21. Experimental Values of Chlorine Toxic Load Exponent from Previous Studies (cont.) • Weedon et al. (1940) was not included in this group • Gas to death to study • Only involved 16 rats and 8 mice • n roughly equals 1.8 • One human study (non-lethal, threshold effects) involved exposures at several exposure durations—Anglen (1981) • n = 1.9 UNCLASSIFIED/UNLIMITED

  22. Human Estimates of Chlorine Toxic Load Exponent from Previous Studies • ten Berge and van Heemst (1983) • Took average of values from Bitron and Aharonson (1978) and Anglen (1981) for a value of n = 2.75 • Right answer for wrong reason? • Should not mix toxic load exponents from two different toxic mechanisms • Systemic respiratory poisoning (Bitron and Aharonson) • Eye and throat irritation (Anglen) UNCLASSIFIED/UNLIMITED

  23. Human Estimates of Chlorine Toxic Load Exponent from Previous Studies (cont.) • Withers and Lees (1985) • Took average of values from Bitron and Aharonson (1978) and Weedon et al. (1940) for a value of n = 2 • However, Bitron and Aharonson is far superior to Weedon et al. • Number of animals (476 (BA) versus 24 (W)) • Gas and observed (BA) versus gas to death (W) • MHAP and Harris and Moses (1983) concluded that n = 2.75 is the best value based upon their separate reviews of all the known chlorine lethality data UNCLASSIFIED/UNLIMITED

  24. Human Estimates of Chlorine Toxic Load Exponent from Present Study • A value of 2.75 is recommended for the human estimate • This estimate is based upon three factors • Bitron and Aharonson (1978) is the only previous experimental study that produced suitable data for a toxic load exponent • n = 3.36 (95% CI of 2.99 to 3.73) (based on re-calculation of original BA data) • Toxic load exponent value from allometric fit of total mammalian lethality dataset (present study) • n = 2.7 (with 95% CI of 2.1 to 4.0) • Error bars overlaps the value of Bitron and Aharonson • The need for caution • Have only one TLE value available from acceptable experimental work • Too high of a TLE value for human estimate will underestimate chlorine toxicity at longer exposure durations • The value of 2.75 was chosen as a conservative estimate • Additional experimental work is needed UNCLASSIFIED/UNLIMITED

  25. Human Estimate of Chlorine Toxicity from Present Study (Military) • YN is a normit • YN = -1, 0 and 1 for 16, 50 and 84% response, respectively • Probit slope • Slope (kTL) equals 2.91 for toxic load basis • Slope (kC) equals 8.0 for vapor concentration basis • kC = n x kTL • C is in mg/m3 and T is in minutes UNCLASSIFIED/UNLIMITED

  26. Human Estimate of Chlorine Toxicity from Present Study (General Population) • Derived from military estimate using the method of Crosier (2007) • YN is a normit • YN = -1, 0 and 1 for 16, 50 and 84% response, respectively • Probit slope • Slope (kTL) equals 2.18 for toxic load basis • Slope (kC) equals 6.0 for vapor concentration basis • kC = n x kTL • C is in mg/m3 and T is in minutes UNCLASSIFIED/UNLIMITED

  27. Chlorine Toxicity Estimates from Present Study and Modified Rijnmond Report (General Population) Present Study Rijnmond Report (Modified) • Upper bound on estimate • Assumes toxicity can be modeled allometrically • Human toxicity closer to that of larger mammals in dataset • Lower bound on estimate • Probit slope was modified from original Rijnmond equation to match that of present work • Assumes human toxicity should be modeled as an average of existing mammalian data UNCLASSIFIED/UNLIMITED

  28. Median Lethal Dosage as a Function of Exposure Duration for Chlorine Inhalation UNCLASSIFIED/UNLIMITED

  29. Sensitivity Analysis of New Human Estimates via ATD Model Runs • Comparison of the historical record versus model predictions of the probability of lethality as a function of downwind distance • Scenario modeled using HPAC • Catastrophic release of 50 tons of chlorine liquid • Flat and open terrain • Three different atmospheric conditions • Low wind (1 m/sec), clear sky, nighttime (2 am), “stable” condition • Pasquill Stability Category F—produced the longest downwind distances • Moderate wind (5 m/sec), cloudy day, “neutral” condition • Pasquill Stability Category D • Low wind (2 m/sec), clear sky, daytime (2 pm), “unstable” condition • Pasquill Stability Category B UNCLASSIFIED/UNLIMITED

  30. Sensitivity Analysis of New Human Estimates via ATD Model Runs (Cont) • HPAC output • Concentration time history for each model run at downwind distances of 0.2 km, 0.5 km, 1.0 km, 1.5 km and 2.0 km along center-line of plume • Histories were then numerically integrated using several different human toxicity estimates • Present study • Previous studies • Modification of present study—examine the sensitivity of plots to changes in toxicity parameters • 2 x 2 matrix of toxic load exponent values and probit slopes • Produced plots of probability of lethality as function of downwind distance UNCLASSIFIED/UNLIMITED

  31. Probability of Lethality as a Function of Downwind Distance--Comparison of Several Toxicity Estimates • Based on concentration-time profile from HPAC simulation • 50 ton release of chlorine • PS Category F • Several toxicity equations used to translate profile into lethality probability • Historical industrial record • Almost no deaths beyond 0.4 km UNCLASSIFIED/UNLIMITED

  32. Probability of Lethality as a Function of Downwind Distance--Comparison of Better Toxicity Estimates • Based on concentration-time profile from HPAC simulation • 50 ton release of chlorine • Two extremes of atmospheric stability • Several toxicity equations used to translate profile into lethality probability • Historical industrial record • Almost no deaths beyond 0.4 km UNCLASSIFIED/UNLIMITED

  33. Toxicity Parameter Sensitivity Analysis • Lethality probability (probability scale) versus log(Downwind Distance) plots • Two by two matrix of low and high values for probit slope and TLE • Probit slope values of 3 and 6 • TLE values of 1.85 and 2.75 UNCLASSIFIED/UNLIMITED

  34. Probability of Lethality as a Function of Downwind Distance—Probit Slope and TLE • Based on concentration-time profile from HPAC simulation • 50 ton release of chlorine • PS Category F • Two by two matrix • PS of 3 and 6 • TLE of 1.85 and 2.75 • All toxicity curves share a common LC50 value at 2 minutes • 4750 mg/m3 • Historical industrial record • Almost no deaths beyond 0.4 km UNCLASSIFIED/UNLIMITED

  35. Summary • Reasonable bounds on the estimate for human chlorine lethality for the general population have been established • Present study (upper boundary) • Allometric fit • Modified Rijnmond Report (lower boundary) • Human equivalent to average of all mammals • Quantitative estimate for the probit slope was derived • Weighted average of experimental probit slopes has not been done previously • Defensible value derived for toxic load exponent • Based primarily on value from Bitron and Aharonson • Collaboration from allometric fit from present study • ATD model using new lethality estimate provides reasonable predictions of downwind distance of lethality plumes UNCLASSIFIED/UNLIMITED

  36. E(CnT)XX = kXX or ECTXX = kXX (1/n) * T(n - 1)/n When n equals one, Haber’s Rule is obtained The approach is based more on empirical observations than on basic biological theories Equation needs to be derived empirically on an individual toxicant basis from acute toxicity experiments where both C and T are varied n is also dependent on the toxicological endpoint, poisoning mechanism, route of exposure, etc. Biologically, it has been postulated that n provides an empirical measure of the agent’s detoxification rate n > 1 corresponds to significant detoxification Operationally, n is also dependent on the exposure scenario Post-exposure decontamination Absence or presence of clothing (in case of percutaneous exposures) Dependence of Toxic Effect on Duration—Toxic Load Model UNCLASSIFIED/UNLIMITED

  37. Anatomy of a Bell Curve Base Equation Z standard normal random variable UNCLASSIFIED/UNLIMITED

  38. Normit Transformation of Percent Response Curve Parameters Median Effective Dose ED50 = 100 Probit Slope m = 3 UNCLASSIFIED/UNLIMITED

  39. Example of Probit Analysis from ECBC Low Level Toxicology Program Quantal Data Red Quantal Points are Off-Scale Median Effective Dosage LCT50 = 231 mg-min/m3 Probit Slope m = 14.1 Percent Lethality versus GB Concentration-Time (mg-min/m3) Female Sprague-Dawley Rats (GB Inhalation, 10 Minutes) From Mioduszewski, et al. (2001) UNCLASSIFIED/UNLIMITED

  40. (CT)1 (CT)2 Toxic Load Model versus Haber’s Rule Toxic Load (TL) Toxic Load Ratio (TLR) If N = 1, Above Equation Reduces Haber’s Rule (CT)1 = (CT)2 Real Life Toxicology Laboratory If TLR  1 (CNT)1 (CNT)2 If TLR = 1 (CNT)1= (CNT)2 Physiological effects from dosage (CT)1 may differ from dosage (CT)2 UNCLASSIFIED/UNLIMITED

  41. Subpopulation-Population RelationshipCrosier Model • Final product the result of a series of three reports • Crosier and Sommerville (2002), ECBC-TR-224, AD A400214 • Crosier (2003), ECBC-TR-337, AD A417162 • Crosier (2007), ECBC-TR-534, AD A465827—final version of model • Premises of mathematical model • The distribution of log(doses) for a healthy subpopulation is located completely within the distribution formed by the general population • Distribution of the log(doses) for the two populations are normal • However, based on theory, the subpopulation cannot be normal, but the normal distribution has been shown by Crosier (2007) to be an useful approximation for the subpopulation • To use model, only three parameters are needed • Percent size of subpopulation relative to the total population—subpopulation healthy enough for military service estimated to equals 30% of total population • Probit slope and median effective dosage for one of the populations UNCLASSIFIED/UNLIMITED

  42. Feasible value pairs do not always produce realistic distributions (see ) Examples of Possible Relative Positions of Subpopulation and Population Bell Curves Centroid Max Mean Max Ratio Editor Subpopulation Distributions (Shaded Areas) as Function of Subpopulation Mean & St. Dev. UNCLASSIFIED/UNLIMITED

  43. Editor Model—located at yellow cross Max difference in means between two bells, with subpopulation distribution still approximately normal Location: SP Standard Deviation: 0.744 SP Mean: 0.900 Tail Model—located at upper end of dashed line This is the point providing the greatest difference in means between the two bell curves However, subpopulation deviates extremely from a normal distribution Editor Final Recommended Position for Relative Positions of Subpopulation and Population Bell Curves UNCLASSIFIED/UNLIMITED

More Related