The structure of current water-soluble radiocontrast media (RCM) is based on fully substituted benzoic acid with three iodines at positions 2, 4, and 6 on the benzene ring (Hong SJ, Wong JT 2002 Allergy Asthma Proc; Pasternak JJ and Williamson EE 2012 Mayo Clin Proc; Szebeni J 2004 Curr Allergy Asthma Rep). The ionic monomers are sodium or meglumine salts of the anionic triiodinated benzene ring and they render with high osmolarity (>1400 mOsm/kg). The dimerized derivatives already have lower osmolarity (eg, 600 mOsm/kg), and further derivatization with hydroxyl groups or other hydrophilic conjugates results in even lower-osmolarity (500–700 mOsm/kg) or isoosmolarity (Hong SJ, Wong JT 2002 Allergy Asthma Proc) resulting in a lack of ionization as shown in table 188.8.131.52.
Although intravenous use of RCMs is routine medical practice today (Szebeni J 2004 Curr Allergy Asthma Rep), they still carry a significant risk for hypersensitivity reactions (HSRs), also referred to as “RCM reactions”(Szebeni J 2004 Curr Allergy Asthma Rep; Szebeni J 2005 Toxicology; Szebeni J 2001 Crit Rev Ther Drug Carrier Syst). It has been proposed in several studies that nonionic, low-osmolarity RCMs (LO-RCM) are safer than ionic, high osmolarity agents (HO-RCM) (Hong SJ, Wong JT 2002 Allergy Asthma Proc; Henry DA, Evans DB 1991 Med J Aust; Westhoff-Bleck M, Bleck JS 1991 Drug Saf; Katayama H, et al. 2001 Invest Radiol; Barrett BJ, et al. 1992 N Engl J Med).
Mast cells and basophils are in the centre of RCM reactions (Szebeni J 2004 Curr Allergy Asthma Rep; Szebeni J 2005 Toxicology; Szebeni J 2001 Crit Rev Ther Drug Carrier Syst). They can be triggered by RCM molecules directly, through intracellular interactions and/or extracellular physical effects (for example, osmotic stress), or indirectly, via cell membrane receptors (e.g. C5aR and C3aR, FcɛRI) (Szebeni J 2004 Curr Allergy Asthma Rep; Szebeni J 2005 Toxicology). Among these, anaphylatoxin receptors (C5aR and C3aR) seem to have the highest impact since complement activation has been shown as an underlying cause of RMC reactions in several experimental studies (Lasser EC, Sovak M 1976 Radiology; Lang JH, Lasser EC 1976 Invest Radiol) and in clinical observations (Lasser EC, et al. 1980 Invest Radiol; Vandenplas O, et al. 1990 Acta Clin Belg; Lieberman P 1991 Clin Rev Allergy; Small P, et al. 1982 Clin Allergy; Westaby S, et al. 1985 Cardiovasc Res), suggesting that CARPA is a good terminology in the majority of HSRs.
Both the classical and the alternative pathways of the complement system can be activated during the RCM reaction (Lieberman P 1991 Clin Rev Allergy; Napolov Iu K, Bolotova EN 1998 Eksp Klin Farmakol) via physical effects (charge, viscosity, iodine number, hydrophilicity and osmotic pressure) (Lieberman P 1991 Clin Rev Allergy; Napolov Iu K, Bolotova EN 1998 Eksp Klin Farmakol; Vik H, et al. 1995 Acta Radiol Suppl); via uncommon mechanisms, such as non-localized, nonsequential cleavage of C proteins (Kolb WP, Lang JH 1978 J Immunol); via suppression of complement inhibitor factors (Factors H and I) (Lieberman P 1991 Clin Rev Allergy); and via direct action on the thioester bonds of C4 and C3 (Vik H, et al. 1995 Acta Radiol Suppl). Positive feedback can be also provided by co-activation of the coagulation and kinin-kallikrein systems, leading to crossover activation of the complement cascade with depletion of C1INH (Szebeni J 2004 Curr Allergy Asthma Rep; Szebeni J 2001 Crit Rev Ther Drug Carrier Syst; Fattori R, et al. 1994 Eur J Radiol). This means that the in vitro investigations of complement system (link) has a prominent role in the immune toxicity research of RCMs.
As it was mentioned, complement activation exerts its effects mainly in the effector arm of the immune response by mast cells and basophil granulocytes, which provoke the clinical symptoms via releasing secondary mediators, including histamine, tryptase, PAF, LTB2, LTB4, LTC4, LTD4, LTE4, TXA2, PGD2 and TXD4 (Westhoff-Bleck M, Bleck JS 1991 Drug Saf; Lieberman P 1991 Clin Rev Allergy; Greenberger PA 1984 J Allergy Clin Immunol). SeroScience offers the measurements of some of these mediators’ derivatives (link), and also offer tests for the investigation of basophil functions both in vitro (link) and in vivo (link). It must be noted that the secretory response of mast cells and basophils to RCM is dependent on the localization of these cells. For example, mast cells from the skin might not respond to certain RCM, whereas pulmonary and cardiac mast cells are triggered for strong release of inflammatory mediators (Genovese A, et al. 1996 Int J Clin Lab Res) by the same RCM.
Hong SJ, Wong JT and Bloch KJ, Reactions to radiocontrast media. Allergy Asthma Proc, 2002. 23(5): p. 347-51.
Pasternak JJ and Williamson EE, Clinical pharmacology, uses, and adverse reactions of iodinated contrast agents: a primer for the non-radiologist. Mayo Clin Proc, 2012. 87(4): p. 390-402.
Szebeni J, Hypersensitivity reactions to radiocontrast media: the role of complement activation. Curr Allergy Asthma Rep, 2004. 4(1): p. 25-30.
Szebeni J, Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology, 2005. 216(2-3): p. 106-21.
Szebeni J, Complement activation-related pseudoallergy caused by liposomes, micellar carriers of intravenous drugs, and radiocontrast agents. Crit Rev Ther Drug Carrier Syst, 2001. 18(6): p. 567-606.
Henry DA, Evans DB and Robertson J, The safety and cost-effectiveness of low osmolar contrast media. Can economic analysis determine the real worth of a new technology? Med J Aust, 1991. 154(11): p. 766-72.
Westhoff-Bleck M, Bleck JS and Jost S, The adverse effects of angiographic radiocontrast media. Drug Saf, 1991. 6(1): p. 28-36.
Katayama H, et al., Iomeprol: current and future profile of a radiocontrast agent. Invest Radiol, 2001. 36(2): p. 87-96.
Barrett BJ, et al., A comparison of nonionic, low-osmolality radiocontrast agents with ionic, high-osmolality agents during cardiac catheterization. N Engl J Med, 1992. 326(7): p. 431-6.
Lasser EC, Sovak M and Lang JH Development of contrast media idiosyncrasy in the dog. Radiology, 1976. 119(1): p. 91-5.
Lang JH, Lasser EC and Kolb WP Activation of serum complement by contrast media. Invest Radiol, 1976. 11(4): p. 303-8.
Lasser EC, et al., Changes in complement and coagulation factors in a patient suffering a severe anaphylactoid reaction to injected contrast material: some considerations of pathogenesis. Invest Radiol, 1980. 15(6 Suppl): p. S6-12.
Vandenplas O, et al., Fulminant pulmonary edema following intravenous administration of radiocontrast media. Acta Clin Belg, 1990. 45(5): p. 334-9.
Lieberman P, Anaphylactoid reactions to radiocontrast material. Clin Rev Allergy, 1991. 9(3-4): p. 319-38.
Small P, et al., Prophylactic antihistamines in the management of radiographic contrast reactions. Clin Allergy, 1982. 12(3): p. 289-94.
Westaby S, et al., Angiography and complement activation. Evidence for generation of C3a anaphylatoxin by intravascular contrast agents. Cardiovasc Res, 1985. 19(2): p. 85-8.
Napolov Iu K, Bolotova EN and Shimanovskii NL [The complement-activating action of modern x-ray contrast agents]. Eksp Klin Farmakol, 1998. 61(2): p. 60-4.
Vik H, et al., Complement activation and histamine release following administration of roentgen contrast media. Acta Radiol Suppl, 1995. 399: p. 83-9.
Kolb WP, Lang JH and Lasser EC Nonimmunologic complement activation in normal human serum induced by radiographic contrast media. J Immunol, 1978. 121(4): p. 1232-8.
Fattori R, et al., Iomeprol and iopamidol in cardiac angiography: a randomised, double-blind, parallel-group comparison. Eur J Radiol, 1994. 18 Suppl 1: p. S61-6.
Greenberger PA, Contrast media reactions. J Allergy Clin Immunol, 1984. 74(4 Pt 2): p. 600-5.
Genovese A, et al., Contrast media are incomplete secretagogues acting on human basophils and mast cells isolated from heart and lung, but not skin tissue. Int J Clin Lab Res, 1996. 26(3): p. 192-8.