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Protein adducts in plasma as biomarkers of exposure to and risk of organic acid anhydrides

Rosqvist, Seema LU (2001)
Abstract (Swedish)
Popular Abstract in Swedish

Stora mängder reaktiva lågmolekylära ämnen används i den kemiska industrin vid produktionen av varor som hanteras i vårt dagliga liv. Exempel på sådana kemikalier är organiska syraanhydrider (OAA). En stor andel av de arbetare som exponeras för dessa viktiga industriella föreningar blir tyvärr sjuka med symtom som astma och hösnuveliknande besvär. I åtminstone en del fall är sjukdomen allergiskt betingad. För att effektivt skydda arbetarna måste man veta vilka exponeringsnivåer som ger upphov till sjukdom, det vill säga vad som vanligen brukar benämnas som exponerings-responssamband. För två OAA, hexahydroftalsyra-anhydrid (HHPA) och metylhexahydroftalsyra-anhydrid (MHHPA), som främst används för... (More)
Popular Abstract in Swedish

Stora mängder reaktiva lågmolekylära ämnen används i den kemiska industrin vid produktionen av varor som hanteras i vårt dagliga liv. Exempel på sådana kemikalier är organiska syraanhydrider (OAA). En stor andel av de arbetare som exponeras för dessa viktiga industriella föreningar blir tyvärr sjuka med symtom som astma och hösnuveliknande besvär. I åtminstone en del fall är sjukdomen allergiskt betingad. För att effektivt skydda arbetarna måste man veta vilka exponeringsnivåer som ger upphov till sjukdom, det vill säga vad som vanligen brukar benämnas som exponerings-responssamband. För två OAA, hexahydroftalsyra-anhydrid (HHPA) och metylhexahydroftalsyra-anhydrid (MHHPA), som främst används för framställning av elektroniska komponenter, finns mycket lite sådan data. Detta förhindrar att ett hygieniskt gränsvärde kan tas fram. Målet med den här studien var att utveckla en metod för att mäta exponeringen för HHPA och MHHPA samt att med hjälp av denna ta fram exponerings-responssamband för dessa anhydrider. Den metod som utvecklades för att mäta exponeringen baseras på analys av de anhydrider som bundit till protein i plasman hos arbetarna, så kallade proteinaddukter. Metoden använder sig av en avancerad och mycket känslig analysmetodik som kallas gaskromatografimasspektro-metri. Det visas i avhandlingen att halten av proteinaddukterna är ett bra mått på exponeringen för anhydrid under mer än en månad tillbaka och att serumalbumin är det protein i plasma som huvudsakligen bildar addukter med syraanhydriderna. Vidare insamlas i avhandlingen plasma från 141 arbetare som exponeras för HHPA och MHHPA och halterna av protein-addukter bestäms i dessa. Utöver detta studeras de arbets-relaterade symptom arbetarna har samt halterna av antikroppar specifika mot anhydriderna vilket kan vara ett tecken på allergisk sjukdom. Halterna av syraanhydridaddukter relateras sedan till antikroppsnivåerna och symtom varvid det visade sig att även en ytterst låg exponering för åtminstone HHPA ökar risken för att utveckla sjukdom betydligt. Slutligen lämnas ett förslag till biologiskt gränsvärde för anhydriderna. (Less)
Abstract
Organic acid anhydrides (OAAs) are important industrial chemicals but also potent inducers of airways diseases. Many exposed workers develop specific IgE and IgG antibodies. Hexahydrophthalic anhydride (HHPA) and methylhexahydrophthalic anhydride (MHHPA) are two particularly sensitising OAAs. The aim of this thesis was to develop and evaluate a method for biological monitoring of exposure to and risk of HHPA and MHHPA, using protein adducts in plasma as biomarkers. A total of 141 workers exposed to HHPA and MHHPA and two guinea pigs exposed to HHPA were investigated. Plasma from these were dialysed and the total plasma protein adducts (TPPA) of the anhydrides were hydrolysed. The acids thus formed were extracted, derivatised and analysed... (More)
Organic acid anhydrides (OAAs) are important industrial chemicals but also potent inducers of airways diseases. Many exposed workers develop specific IgE and IgG antibodies. Hexahydrophthalic anhydride (HHPA) and methylhexahydrophthalic anhydride (MHHPA) are two particularly sensitising OAAs. The aim of this thesis was to develop and evaluate a method for biological monitoring of exposure to and risk of HHPA and MHHPA, using protein adducts in plasma as biomarkers. A total of 141 workers exposed to HHPA and MHHPA and two guinea pigs exposed to HHPA were investigated. Plasma from these were dialysed and the total plasma protein adducts (TPPA) of the anhydrides were hydrolysed. The acids thus formed were extracted, derivatised and analysed by gas chromatography-mass spectrometry (GC-MS). Air levels and urinary metabolite levels of the anhydrides were also analysed by GC methods. Chromatography, electrophoresis and immunological methods were used for separation, identification and quantification of proteins and Igs. Medical histories and symptoms were assessed through questionnaires supplemented with interviews and medical examinations. A quick, simple, accurate, precise and sensitive quantification method for TPPA of OAAs was developed. There were very strong correlations between long-term exposures, as assessed by repeatedly collected urine samples and hemoglobin adducts, and TPPA. Serum albumin (SA) was found to be the major OAA adduct forming protein. Anhydride specific IgE and IgG showed a preferred affinity for SA adducts. There were significant exposure-response relationships for TPPA of HHPA with specific IgE and IgG and symptoms and for TPPA of MHHPA with specific IgG. Thus, the TPPA can be considered to be excellent biomarkers of long-term exposure and of risk. A biological occupational exposure limit for HHPA and MHHPA is suggested. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Drexler, Hans, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine,University of Erlangen-Nürenberg, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
GC-MS, IgG, IgE, exposure-response, serum albumin, biological monitoring, Hexahydrophthalic anhydride, methylhexahydrophthalic anhydride, OEL, Occupational health, industrial medicine, Yrkesmedicin, arbetsmiljömedicin
pages
100 pages
defense location
N/A
defense date
2001-10-11 13:15
ISBN
91-628-4908-5
language
English
LU publication?
yes
id
85910667-0245-4bf4-9d96-7f245987b347 (old id 41834)
date added to LUP
2007-06-20 10:43:42
date last changed
2016-09-19 08:45:16
@phdthesis{85910667-0245-4bf4-9d96-7f245987b347,
  abstract     = {Organic acid anhydrides (OAAs) are important industrial chemicals but also potent inducers of airways diseases. Many exposed workers develop specific IgE and IgG antibodies. Hexahydrophthalic anhydride (HHPA) and methylhexahydrophthalic anhydride (MHHPA) are two particularly sensitising OAAs. The aim of this thesis was to develop and evaluate a method for biological monitoring of exposure to and risk of HHPA and MHHPA, using protein adducts in plasma as biomarkers. A total of 141 workers exposed to HHPA and MHHPA and two guinea pigs exposed to HHPA were investigated. Plasma from these were dialysed and the total plasma protein adducts (TPPA) of the anhydrides were hydrolysed. The acids thus formed were extracted, derivatised and analysed by gas chromatography-mass spectrometry (GC-MS). Air levels and urinary metabolite levels of the anhydrides were also analysed by GC methods. Chromatography, electrophoresis and immunological methods were used for separation, identification and quantification of proteins and Igs. Medical histories and symptoms were assessed through questionnaires supplemented with interviews and medical examinations. A quick, simple, accurate, precise and sensitive quantification method for TPPA of OAAs was developed. There were very strong correlations between long-term exposures, as assessed by repeatedly collected urine samples and hemoglobin adducts, and TPPA. Serum albumin (SA) was found to be the major OAA adduct forming protein. Anhydride specific IgE and IgG showed a preferred affinity for SA adducts. There were significant exposure-response relationships for TPPA of HHPA with specific IgE and IgG and symptoms and for TPPA of MHHPA with specific IgG. Thus, the TPPA can be considered to be excellent biomarkers of long-term exposure and of risk. A biological occupational exposure limit for HHPA and MHHPA is suggested.},
  author       = {Rosqvist, Seema},
  isbn         = {91-628-4908-5},
  keyword      = {GC-MS,IgG,IgE,exposure-response,serum albumin,biological monitoring,Hexahydrophthalic anhydride,methylhexahydrophthalic anhydride,OEL,Occupational health,industrial medicine,Yrkesmedicin,arbetsmiljömedicin},
  language     = {eng},
  pages        = {100},
  school       = {Lund University},
  title        = {Protein adducts in plasma as biomarkers of exposure to and risk of organic acid anhydrides},
  year         = {2001},
}