Simulated biological fluids – a systematic review of their biological relevance and use in relation to inhalation toxicology of particles and fibres

Figures & data

Figure 1. Schematic highlighting the pathogenicity pathways of (a) fibres inside the alveolar space interacting with macrophages; (b) poorly soluble metals remaining in the alveolar space, alongside transfer through cellular mechanisms; and (c, d) soluble metals in intra- and extra-cellular regions.

Figure 2. Schematic demonstrating the diversity of simulated biological fluids and the differences in their composition and physiochemical properties. In particular, the alveoli and lysosome have been highlighted indicating the locations and characteristics of the lysosomal fluid, lung lining fluid and interstitial fluid. [adapted with permission from (Plumlee et al. 2006)].

Table 1. Composition (g/L) of frequently used biofluids used to simulate the neutral conditions of the lung lining fluid.

Biofluid name	Original Gamble’s solution	Modified Gamble’s solution / AIF	Gamble’s serum simulant	Gambles solution	Modified low calcium Gambles solution*	Modified SLF	Modified Gamble;s media	Hatch’s solution	Ringer’s solution	SELF	SILF	SUF	AAF	SILF [mSILF]	SLF
Reference (I–XV)	I	II	III	IV	V	VI	VII	VIII	IX	X	XI	XII	XIII	XIV	XV
Sodium chloride	6.019	7.120	6.779	6.779	6.600	8.474	6.415	7.0	8.182	6.020	6.019	6.779	6.019	6.019	6.662
Ammonium chloride			0.534									0.535
Sodium bicarbonate	2.604	1.950	2.268	0.504	2.703	2.016	2.703	2.270	0.084	2.700	2.604	2.268	2.604	2.604
Dibasic sodium phosphate	0.142	0.148	1.439	0.214^†	0.358^‡	0.178^†	0.358^‡	0.120		0.150			0.142	0.268	1.107
Sodium dihydrogen phosphate monohydrate											0.126	0.144
Sodium citrate	0.097^†	0.152^†	0.052	0.348^¶	0.153^†	0.104^¶					0.097^†	0.052	0.097^†	0.097	0.088^†
Sodium tartrate dihydrate		0.180			0.180
Nax citrate and tartrate and lactate and pyruvate^§							0.680
Calcium chloride	0.368^†	0.029^†	0.022	0.044^ǁ	0.022	0.263^ǁ	0.193 or 0.022	0.225	0.222	0.256^†	0.368^†	0.022	0.368^†	0.368
Glycine		0.118	0.450		0.118		0.118			0.376		0.375
l-Cysteine			0.121							0.122		0.240^#
Potassium chloride	0.298			0.746		0.298		0.370	0.149	0.298	0.298		0.298	0.298
Potassium dihydrogen phosphate								0.030
Potassium phosphate monobasic															0.299
Concentrated sulphuric acid												0.049
Magnesium sulphate								0.034
Magnesium chloride	0.203^ǁ	0.212^ǁ		2.571	0.212^ǁ	0.095	0.212^ǁ	0.210^ǁ		0.200^ǁ	0.095		0.203^ǁ	0.203
D-Glucose								1.000
Sodium sulphate	0.071	0.079			0.079	0.071	0.079			0.072	0.063		0.071	0.071
Sodium acetate	0.953**			0.016		0.574					0.574		0.953**	0.952
Sodium pyruvate		0.172			0.172
Sodium lactate					0.175
Lactic acid (90%)		0.156
Phosphatidyl choline								10.00					0.100
α-Tocopherol								0.001
Uric acid								0.025		0.016					0.019 (sodium salt)
Serum albumin								10.00
Albumin										0.260
Mucin										0.500
Lysozyme								2.500
Apo-transferrin								0.200
Ascorbic acid								0.050		0.018					0.035
Glutathione								0.050		0.030					0.031
DTPA												0.787
ABDC												50 ppm
DPPC														[0.02% w/v]
Benzalkonium chloride

*1–1.5 ml of hydrochloric acid added.

^†Dihydrate.

^‡Dodecahydrate.

^¶Pentahydrate.

^§No information on the breakdown of these components was provided.

^ǁHexhydrate.

^#l-Cysteine hydrochloride.

**Trihydrate.

I: Moss (1979); Berlinger et al. (2008); II: Christensen et al. (1994); Stopford et al. (2003); III: Ansoborlo et al. (1990); IV: Garger et al. (2013); V: Sebastian et al. (2002); VI: Garger et al. (2013); VII: Lehuede et al. (1997); VIII: Berlinger et al. (2008); IX: Aladova et al. (2007); Garger et al. (2013); X: Boisa et al. (2014); XI: Costabile et al. (2015); XII: Eidson and Griffith (1984); Cheng et al. (1997); Cheng et al. (2004); XIII: Semisch et al. (2014); XIV: Davies and Feddah (2003); Son and McConville (2009); Ungaro et al. (2009); Spitler et al. (2015); XV: Charrier et al. (2014); Kuang et al. (2017).

Table 2. Composition (g/L) of frequently used biofluids for simulation of the acidic conditions of the lysosome.

Biofluid name	Intracellular fluid*	ALF	PSF	PSF	Modified (low calcium) Gamble’s solution^†	Lyso-SBF^‡
Reference (I–VI)	I	II	III	IV	V	VI
Sodium chloride	3.210	3.210	7.013	6.650	7.120
Sodium bicarbonate					1.950
Dibasic sodium phosphate	0.179^¶	0.071	0.284	0.142	0.148
Sodium citrate dihydrate	0.077	0.077			0.152
Sodium tartrate dihydrate	0.090	0.090			0.180
Sodium lactate	0.085	0.085
Sodium pyruvate	0.086	0.086			0.172
Calcium chloride	0.097	0.128^§	0.277	0.029^§	0.029^§	0.055
Glycine	0.059	0.059	0.450	0.450	0.118
Sodium hydroxide	6.000	6.000
MES-sodium hydroxide						5.883
Magnesium chloride	0.106^ǁ	0.050			0.212^ǁ	0.095
Potassium chloride						14.91
Glucose
Sodium sulphate	0.039	0.039	0.071	0.071	0.079
Lactic acid (90%)					0.156
Citric acid	20.80	20.80
Potassium hydrogen phthalate			4.901	4.085
ABDC			50 ppm	50 ppm

*The original formulation later defined as ALF

^†Addition of 3.7–5 ml/L concentrated hydrochloric acid to reduce pH to 4.5

^‡pH of 5.2

^¶Dodecahydrate

^§Dihydrate

^ǁHexhydrate

I: Thelohan and de Meringo (1994); II: Hedberg et al. (2010); Figueroa-Lara et al. (2019); III: Aladova et al. (2007); IV: Stefaniak et al. (2005); Stefaniak et al. (2009); Stefaniak et al. (2010); Stefaniak et al. (2014); V: Christensen et al. (1994); Sebastian et al. (2002); VI: Muller et al. (2010).

Figure 3. Selected mechanisms that effect dissolution on the surface of a particle including: (a) complexation, (b,c) redox activities, (d) proton-promoted dissolution and (e) enzymatic action. The prevalence of each dissolution mechanism will be material specific, driven by the chemistry of the materials surface.

Table 3. Correlation of results from in vitro acellular assays with measurements taken in vivo or within cells grown in vitro.

Ref.	Description of study	Material	Correlation
Extracellular fluid
Chazel et al. (2000); Chazel et al. (2003)	Comparison of results from intratracheal instillation (male, Sprague-Dawley rats) with static dissolution in: (a) Gamble’s solution; (b) CCM	UF4	(a) + (b) −
Zhong et al. (2020)	Comparison of results from intranasal instillation (female Balb/c mice) with static dissolution in: (a) Gamble’s solution; (b) SLF; (c) SELF	PM2.5 spiked with Pb compounds	−
Luoto et al. (1994)	Comparison of dissolution in alveolar macrophage cell culture with dissolution in Gamble’s solution	MMVF	−
Lehuede et al. (1997)	Compositional changes observed in the rat inhalation studies compared to those observed when incubated in Gamble’s	MMMF	+
Intracellular fluid
Hamilton et al. (2018)	Comparison of dissolution in ALF to results observed in primary C57B1/6 murine alveolar macrophages	Ag NPs	+
MilosevicAc et al. (2019)	Comparison of dissolution in ALF to results from mouse macrophage (J774A.1) cells	Au NPs	+
Latvala et al. (2016)	Comparison of dissolution in ALF and toxicity in human type II alveolar epithelial (A549) cells	Ni metal	−
Colombo et al. (2008); Artelt et al. (1999)	Comparison of two separate studies: In vitro dissolution of road side dust samples in ALF (Colombo et al. 2008) Nose-only inhalation study in Lewis rats (4 mg/m^3 for 5 h/day, 5 days/week for 90 days)	Pt-containing roadside dust	+
Stefaniak et al. (2005)	Comparison of static dissolution in PSF with that seen in J774A.1 macrophage cell line	Be metal, BeO	+
Heim et al. (2020)	Comparison of animal mortality to metal alloy powders (nose only inhalation by male dose Sprague-Dawley rats) to alloy solubility and metal ion bioavailability in: (a) interstitial fluid (Gamble’s formulation), or (b) lysosomal fluid (ALF formulation)	Ni metal, Co metal and stainless steel	(a) + (b) −
Zhong et al. (2020)	Comparison of results from intranasal instillation (female Balb/c mice) with static dissolution in ALF	PM2.5 spiked with Pb compounds	−
Guldberg et al. (2002)	Comparison of t½ after intratracheal instillation or inhalation (rats) with flow-through dissolution in modified Gamble’s at pH 4.5	Numerous stone wools	+
Koltermann-Jülly et al. (2018)	Comparison of dissolution in PSF to results observed in NR8383 rat macrophages	BaSO4<SrCO3<ZnO	+
Koltermann-Jülly et al. (2018)	Comparison of results from short term inhalation study in rats with dynamic dissolution in PSF	(a) BaSO4, CeO2, CuO, ZnO, SiO2 amino, (b) SiO2 untreated, TiO2	(a) + (b) −
Gray et al. (2018)	Comparison of dissolution in PSF to results observed in J774.A1 murine macrophages	MoO3	+
Keller et al. (2020)	Comparison of results from intratracheal Instillation in rats with (a) dynamic and (b) static dissolution in PSF	BaSO4	(a) + (b) −

(+) implies a good correlation was found and (−) indicates a poor one.

Table 4. Studies comparing “simple” and complex fluids, including an indication of whether the more complex fluid caused less (−), equal (0), or greater (+) dissolution.

Ref.	Description of study	Material	Effect of more complex fluid on dissolution
Extracellular compartments
Son and McConville (2009)	Addition to DPPC to SLF	Hydrocortisone	+
Ungaro et al. (2009)	Addition to DPPC to SILF	Insulin (pulmonary delivery via PGLA)	0
Ansoborlo et al. (1990); Ansoborlo et al. (1992)	Addition of SOD to Gamble’s solution	Uranium compounds	+
Jurinski and Rimstidt (2001)	Dissolution in PBS solution compared against Gamble’s solution	Talc	0
Garger et al. (2013)	Dissolution in Gamble’s solution compared to SUF (containing less salts and no complexation agents)	Plutonium oxide	−
Berlinger et al. (2008); Kastury et al. (2018a), Vitarella et al. (2000)	Dissolution in Gamble’s solution compared to Hatch’s solution (composition includes organic components such as proteins and enzymes)	Metals in the welding fume (Fe, Mn, Cr, Ni, Mo, Ti) (Berlinger et al. 2008) Arsenic and lead (Kastury et al. 2018a) Manganese (Vitarella et al. 2000)	+ + +
Spitler et al. (2015)	Investigated the effect of adding organic components to SILF, namely phospholipids, proteins and lipids naturally present in vivo	Uranium in soil	0
Kumar et al. (2017); Hassoun et al. (2018)	Compared solubility in traditional Gamble’s solution to a more “bio-relevant fluid” including the addition of lipids and proteins including DPPC, dipalmitoylphosphatidylglycerol, cholesterol, 32 albumin, IgG, transferrin and antioxidants (ascorbate, urate and glutathione).	Poorly water-soluble drugs	+
Intracellular compartments
Stebounova et al. (2018)	Comparison of dissolution in ALF with a simplified acidic solution	Manganese NPs	+
Tan et al. (2020)	Comparison of dissolution in ALF (pH 5.0) with pure water and simulated natural water (pH 5.0)	Zinc in particulate matter	+
Stefaniak et al. (2009)	Removal of glycine or phosphate from the PSF composition	Cobalt	0
Commercially available fluids
Chazel et al. (2000)	Comparison of CCM (with 10% foetal calf serum) to Gamble’s solution	Uranium tetrafluoride	− (<3 days) 0 (Day 7) + (>7 days)
Ansoborlo et al. (1992)	Comparison of EBM to Gamble’s solution	Uranium trioxide	+
Semisch et al. (2014)	Comparison of artificial alveolar fluid (AAF), water and DMEM (complex fluid) with and without FCS.	Copper oxide	+

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